Indo American Journal of Pharmaceutical Research, 2013
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ISSN NO: 2231-6876
INDO AMERICAN JOURNAL OF PHARMACEUTICAL RESEARCH
EFFECTS OF PARTICLE SIZE AND SOME FORMULATION ADDITIVES ON THE DISSOLUTION PROFILE OF IBUPROFEN FROM COMPRESSED TABLETS. Umeh O.N.C.*,Orji I.E,Ofoefule S.I. Department of Pharmaceutical Technology and Industrial Pharmacy,University of Nigeria, Nsukka ARTICLE INFO Article history Received 05/09/2013 Available online 31/01/2014
Keywords Ibuprofen, SLS, Ac-Di-SOL, Primogel R, disolution efficiency, enhancement.
ABSTRACT Drugs of low aqueous solubility provide a major challenge in the design of modern oral dosage form due to dissolution and bioavailabilty difficulties. The present study was undertaken to investigate the effect of particle size and some formulation additives (sodium laurylsulphate (SLS), Primogel R and Ac-Di-Sol) on the release profile of poorly soluble drug, ibuprofen from compressed tablets. Six batches (A - F) of Ibuprofen granules and tablets were prepared by the wet granulation method. Batches A, B and C contained granules that were fractionated from three sieve fractions (0.42, 0.25 and 0.15 mm respectively) in ascending order of particle size. D, E and F contained 2 % Primogel R, 1 % Ac-Di-Sol and 0.2 % SLS respectively. Tablet properties evaluated as a function of particle size and formulation additives include: hardness, friability and dissolution efficiency at 60 min. Results obtained indicated a decrease in the dissolution rate of the batches as the particle size increased. All the Ibuprofen tablet batches produced exhibited better drug release (in terms of rate and extent of release) than a commercially available sample, Multifen ®. The overall and expected in vivo bioavailability in the batches on the basis of dissolution efficiency parameter (DE60) is in the order of E (98.3 %) > D (98.0 %) > A (97.7 %) > F (96.9 %) > B (95.3 %) > C (93.8 %) > Multifen® (26.0%). Statistical comparison of the DE60 parameter indicated a significant difference (p ˂ 0.05) in the results from the formulated batches and the commercially available sample, Multifen®. The results indicated that particle size reduction of granules and the inclusion of formulation additives like SLS, Ac-Di-SOL and Primogel R can be utilized in improving the release profile of Ibuprofen from compressed tablets.
Copy right © 2013 This is an Open Access article distributed under the terms of the Indo American journal of Pharmaceutical Research, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
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Please cite this article in press as Umeh O.N.C et al effects of particle size and some formulation additives on the dissolution profile of ibuprofen from compressed tablets .Indo American Journal of Pharm Research.2014:4(01).
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Corresponding author Ogochukwu N.C. Umeh Dept. of Pharmaceutical Technology and Industrial Pharmacy, Faculty of Phamaceutical sciences, University of Nigeria, Nsukka 410001, Enugu state, Nigeria. +2348037989369
[email protected]
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INTRODUCTION Drug absorption from solid dosage form after oral administration depends on the release of the drug substance from the drug product, the dissolution or solubilization of the drug under physiological conditions, and the permeability across the gastrointestinal tract. Many drugs are poorly soluble, and this results in poor bioavailability because solubility is an important factor in determining the rate and extent of their absorption [1]. In vitro dissolution is often applied to predict in vivo drug performance especially in cases of poorly soluble drugs and extended release formulations [2]. Formulation parameters have been identified as one of the factors that influences tablet characteristics. Studies have shown that variations in the manufacturing processes could consistently alter the disintegration, dissolution and consequently the bioavailability of the active ingredients in a product [3]. However, it has also been shown that through physical modifications, the surface area, solubility and wettability of the powder particles can be increased thereby improving dissolution and hence bioavailability of poorly soluble drugs [4]. The incorporation of adjuvants (like diluents, lubricants and surfactants) into tablet formulations can cause significant effects on the dissolution rate of drugs especially those that are hydrophobic and poorly soluble [5]. Therefore the choice of formulation additives is often of critical importance in establishing a successful product for oral administration. Ibuprofen is a non steriodal, antiinflammatory drug (NSAID) used widely in the treatment of a variety of ailments such as arthritis and dysmenorrhoea. It possesses antipyretic and analgesic activities in the case of an inflammatory component. It functions by reducing the hormones causing inflammmation and pain in the body. The drug is absorbed rapidly after oral administration, and peak plasma serum level is generally attained within 1 to 2 h. The serum half-life is 1.8 to 2.0 h [6]. It is practically insoluble in water and its oral absorption is dissolution rate limited which leads to potential bioinequivalence problems [7], [8]. The improvement of ibuprofen dissolution for its immediate release is therefore desirable for rapid absorption which is a prerequisite for the quick onset of its pharmacological actions. Different approaches have been employed to enhance the solubility, dissolution profile and bioavailability of the poorly soluble drug, ibuprofen. The kinetics of ibuprofen dissolution in ionic and non ionic surfactant solutions and the characterization of the formed micellar systems have been reported by Zenon k and Hanna Z [9]. Nafady also earliar investigated the effects of some binding agents and film coating on the mechnical, compressibility and release characteristics of ibuprofen [10]. Ibuprofen solid dispersions using PEG 6000 and PVP K 30 combinations and various other carriers have also been reported to improve dissolution [11], [8], [12], [13], [14]. Dabbagh M and Beitmashal L, have also developed and studied sustained release formulations of ibuprofen and Ibuprofen-HPMC matrix tablets using different drug: polymer ratios, particle sizes and crystal forms [15]. In the present study, the effect of different particle sizes and the comparative performance of three additives (Sodium laurylsulphate (SLS), primogel and Ac-Di-Sol) on the release profile of Ibuprofen from compressed tablet was investigated. In this research, different batches of ibuprofen containing granules fractionated from three sieve fractions (0.42, 0.25 and 0.15 mm) were prepared and evaluated. EXPERIMENTAL Materials Maize starch (May & Baker, England), Ac - Di - SOL (FMC Corp, Philadelphia), talc, magnesium stearate, lactose, Sodium laurylsulphate, Primogel R (Sigma chem co, USA), Ibuprofen is a general gift from SyCom Pharmaceutical, India. All other reagents are of Analar grade.
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Batches Ingredients A (0.2 mm)* B (0.34 mm)* C (0.71 mm)* Ibuprofen (mg) 100 100 100 Starch as disintegrant (%) 10 10 10 Starch as binder (%) 5 5 5 Magnessium stearate (%) 1 1 1 Talc (%) 1 1 1 Lactose (%) 10 10 10 Starch q.s to 300 mg 110 110 110 Primogel (mg)+ 14.3 AC-DI-SOL (mg)+ 7.15 Sodium Laurylsulphate (mg)+ 1.4 + *Particle size of granules Batch D, E, F respectively
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Method Preparation of Ibuprofen Tablets Six batches of Ibuprofen tablets were prepared by wet granulation method according to the composition in Table 1. Ibuprofen powder, maize starch and lactose were mixed and triturated in a mortar to a homogenous mixture. Weighed quantity of maize starch was dispersed in distilled water and heated in a water bath with continual stirring to form a mucilage. The mucilage was incorporated into the powder mixture in a mortar and triturated to a homogenous wet mass. The wet mass was screened through a 1.00 mm stainless steel sieve and dried in the oven at 50 oC for 18 h. The granules were further fractionated into three sieve fractions (0.42, 0.25 and 0.15 mm). The fractions were labelled A, B and C in ascending order of particle size. They were stored in well closed amber coloured bottles for further experiments. Table 1: Formular for preparing Ibuprofen tablets
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Umeh O.N.C et. al.
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Six batches (A-F) of Ibuprofen granules and tablets were prepared using the wet granulation method. Three batches A, B and C were produced from granules that were earliar fractionated into three sieve fractions (0.42, 0.25 and 0.15mm respectively) in ascending order of particle size. The remaining three batches D, E and F were similarly prepared but with different additives (2% Primogel, 1% Ac-Di-Sol and 0.2% SLS). Forty tablets were produced for each batch. Compression of Tablets Prior to compression, all the granule batches were lubricated with 1% magnesium stearate and 1% Talc. Lubricated granules were compressed into tablets using an F-3 Manesty single punch tabletting machine fitted with 9.5 mm flat faced punches. Compression pressure was maintained at a constant pressure unit of the tabletting machine. Forty tablets were produced for each batch. Three granules/ tablet batches containing 2% Primogel R (D), 1% Ac-Di-Sol (E) and 0.2% SLS (F) respectively were similarly prepared. Tablet weights ranged from 295 to 305 mg. Prepared tablets were evaluated for hardness, friability, assay of active ingredients and dissolution profile studies using standard methods [16], [17]. Dissolution Profile studies The Erweka DT dissolution apparatus fitted with a paddle that was operated at 50 rpm was used. The dissolution medium consisted of freshly prepared phosphate buffer (pH 7.2) maintained at 37± 1 oC. A tablet from each batch was placed in a basket (mesh size 325 mm) immersed half way into the dissolution medium. Volumes (5 mL) were withdrawn at predetermined time intervals and replaced with an equal volume of the dissolution medium maintained at the same temperature. Each withdrawn sample was analyzed spectrophometrically at 272 nm using a Pye Cam SP8-1000 UV spectrophometer. From the Beer’s calibration plot, the concentration of ibuprofen released over time was calculated. The percentage amount of ibuprofen released for each batch was plotted against time. The dissolution profile data were fitted into dissolution efficiency equation proposed by Khan and Rhodes [18] as shown in equation 1. (1) Where Q is the drug percent dissolved at time, t and Q max is maximum amount of drug released. The time taken for 50% of ibuprofen to be released from each batch was also noted. In this study, all dissolution efficiencies were obtained at t equal to 60 min. Values plotted are a mean of two replicate determinations. RESULTS AND DISCUSSION The particle size distribution of batches A, B and C had variable effects on the hardness, friability and hardness-friability ratio (HFR) of the tablets (Table 2). According to some previously published work, uncoated tablets with hardness of ≥ 4 kgf are considered adequate for handling and transportation [16], [17]. From the results (Table 2), all the batches except batch B are considered adequate in terms of hardness. The results for friability, indicate that all the batches were within the acceptable limit of ≤ 1% [16], [17]. The values of hardness and friability provide measures of tablet strength and weakness, respectively. The parameter, hardnessfriability ratio (HFR) have been employed as an index to measure the mechanical properties of ibuprofen tablets [19], [20]. The higher the HFR, the stronger the tablet [19], [20]. The assay results of the batches ranged from 71.0 to 91.0% (Table 2 and 3). Table 2: Effect of Particle size on some properties of Ibuprofen tablets.
Particle size A (0.22 mm) B (0.34 mm) C (0.71 mm) *Standard deviations
Parameters Mean weight (mg) Hardness (kgf) Friability (%) 299.90 (1.62)* 4.19 (0.22)* 0.97 300.80 (2.09)* 3.93 (0.17)* 0.85 298.95 (1.19)* 5.02 (0.06)* 0.90 ** Hardness-friability ratio
HFR** 4.32 4.62 5.58
Assay (%) 91.0 76.3 75.2
DE60 (%) 97.3 94.5 96.2
T50% (min) 3.12 3.51 3.52
The values represent the means ± Standard deviations (SD) for 10 tablets per batch. Statistically significant differences between the batches were measured using the Student T-test with SPSS version 16.
HFR** Assay (%) DE60 (%) 5.25 71.00 98.30 6.15 77.80 98.00 5.82 73.70 96.90 72.22 26.00 + Commercially available sample
T50% (min) 2.67 2.91 2.86 -
The values represent the means ± Standard deviations (SD) for 10 tablets per batch. Statistically significant differences between the batches were measured using the Student T-test with SPSS version 16.
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Parameters tested Additives Mean weight (mg) Hardness (kgf) Friability (%) Primogel 298.20 (1.99)* 5.04 (0.05)* 0.96 Ac-Di-Sol 299.55 (1.76)* 5.04 (0.05)* 0.82 SLS 299.40 (2.46)* 5.06 (0.05)* 0.87 Control+ 644.25 (10.71)* 7.10 (0.88)* 0.00 *Standard deviations ** Hardness-friability ratio
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Table 3: Effect of additives on some properties of Ibuprofen tablet
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All the batches except the commercial sample (Multifen®) released up to 50% of ibuprofen within 3.52 min. A graphical representation of the dissolution profile of ibuprofen released over 60 min is shown in Fig.1 and 2.
Fig. 1: Effect Of Particle Size On the Release profiles of Ibuprofen Tablets. The percentage concentration of Ibuprofen released from batches A (─♦─), B (─■─) and C (─▲─) formulations were compared to that of Multifen® (─×─), a commercially available sample. There was a significant increase ((p < 0.05) in the amount of Ibuprofen released from the batches with different particle sizes than from the Multifen® tablets
The percentage concentration of Ibuprofen released from the Primogel (─♦─), Ac-di-sol (─■─) and SLS (─▲─) formulations were compared to that of Multifen ® (─×─), a commercially available sample. There was a significant increase ((p < 0.05) in the amount of Ibuprofen released from the three additives than from the Multifen ® tablets.
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Fig. 2: Effect Of Additives On the Release profiles of Ibuprofen Tablets.
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The release of ibuprofen depended on the particle size distribution of the granules prior to compression and the different additives incorporated in the formulation. In Fig.1, it was observed that as the particle size increased, there was a significant (p > 0.05) decrease in the rate of release of ibuprofen from the tablets in comparison to a commercially available sample (Multifen®). Batch A having a particle size of 0.22 mm exerted a more improved rate of drug release than the other batches. There was a significant increase (p ˂ 0.05) in the dissolution efficiency of batch A when compared to batch C. The ranking of the amounts of ibuprofen dissolved after 60 min from the batches with different particle sizes was in the order of A (97.7%) > B (95.3%) > C (93.8%). The mechanism of improved dissolution by reduction in particle size is usually through the enhancement of drug solubility. This is consistent with the Nernst-Brunner theory that states that dissolution rate is directly proportional to the surface area of a drug [6]. Since the surface area increases with decreasing particle sizes, higher dissolution rates may be achieved through reduction of particle size [6]. Similar findings was observed by Dabbagh [15] using propranolol hydrochloride and HPMC in evaluating ibuprofen-HPMC matrix tablets. Also in earliar studies, several investigations have also demostrated an increased absorption rate for griseofulvin after reduction in particle size (micronization) [6,], [21]. Although it is normally assumed that drug solubility is independent of particle size, drug solubility and surface area have been correlated by the Ostwald-Freundlich equation [6]. Batches D, E and F showed close drug release rates after 60 min (Fig. 2).
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The ranking of the percentage of Ibuprofen dissolved after 60 min from the batches with different additives were 97.90% > 97.30% > 94.60% for E, D and F respectively. These batches gave a statistically significant increase (p ˂ 0.05) in the rate and extent of ibuprofen released than a commercially available sample (Multifen®). The presence of Primogel and Ac-Di-Sol in D and E respectively, was found to have enhanced the disintegration time of the formulation with a resultant increase in its dissolution rate. This is most likely due to the super-disintegrant properties of both additives. The incorporation of 0.2% ( w/w) SLS in F enhanced the rate of release of ibuprofen during the early time points (5 min), with a later statistically significant decrease (p > 0.05) in the rate and extent of release when compared to that of the other batches. This is consistent with several reports that SLS exerts variable effect on drug release when incorporated into formulations [22], [23]. Enhancement as well as inhibition of the GIT absorption and pharmacological activity of drugs have been observed when SLS was added to drug formulations. This is due to the formation of a special type of complexation reaction between the drug and surfactant (SLS) leading to aggregation of the surfactant molecules (micelle formation)[23], [24]. The release / absorption retarding effect usually predominate at higher surfactant concentrations because a larger fraction of the drug is bound to micelles [23], [24]. The expected in vivo bioavailability in the batches on the basis of dissolution efficiency (DE60) parameter is in the order of E(98.3%) > D(98.0%) > A(97.7%), F(96.9%) > B(95.3%) > C(93.8%) > Multifen® (26.0%).
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CONCLUSION The overall results showed the effects of different particle sizes and the presence of different formulation additives on the mechanical strength and release characteristics of ibuprofen from compressed tablets. It was observed that the presence of different formulation additives and distinct particle size distribution of the bulk drug significantly influenced the extent and rate of dissolution of ibuprofen from the prepared tablets. The results suggests that Ac-Di-Sol and primogel could be useful as suitable formulation additives to enhance the solubility and rate of release of poorly soluble Ibuprofen from tablet formulations. This indicates that the used formulation additives are good candidates for the manufacture of ibuprofen tablets. The prepared tablets gave a better dissolution profile than that of the commercially available ibuprofen tablet (Multifen ®) .
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20. Odeku OA, Itiola OA. Evaluation of the effects of Khaya gum on the mechanical and release properties of paracetamol tablets. Drug Dev Ind Pharm 2003;29:311-20. 21. Fell JT, Calvert RT, Rileybenthan P. Bioavailability of griseofulvin from a novel capsule formation. J Pharm Pharmacol 1978;30:479–82. 22. Levy G. Biopharmaceutical considerations in dosage form design and eveluation. In: JR Sprowls, editor. Prescription Pharmacy, 2nd ed. Philadelphia: JB Lippincott Co.; 1970. p.72-3. 23. Umeh ONC, Emeje MO, Ofoefule SI. The effect of some channeling agents on the release of diclofenac potassium from a hydrophobic polymer matrix. Res J Pharm Biol Chem Sci 2012;3:1173-7. 24. Ofoefule SI and Chukwu A. Effects of Polyethylene glycol 4000 and Sodium laurylsulphate (SLS) on the release of hydrochlorthiazide (HCTZ) embedded in dika fat matrix. Acta Pharm 2001;8:233-9.
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