Aly Nada is an associate professor and chairman at the Department of Pharmaceutics, Faculty of Pharmacy, Kuwait University, PO Box 24923 Safat, 13110 Kuwait, tel. 00965 4986072, fax: 00965 4986843, 

Aly Nada

Ketorolac tromethamine (KT), (±)-5-Benzoyl-2,3-dihydro-1H-pyrrolizine-1-carboxylic acid compound with 2-amino-2-(hydroxymethyl)-1,3-propanediol (in 1:1 ratio), is a potent nonsteroidal anti-inflammatory  drug (NSAID) without an opioid effect. It is a pyrrolizine carboxylic acid derivative, chemically related to indomethacin and tolmetin (1).  

KT is indicated for the short-term management of moderately severe acute pain that would otherwise require treatment with an opioid analgesic. Like other NSAIDs, KT inhibits the activity of the enzyme cyclo-oxygenase, leading to decreased formation of precursors of prostaglandins and thromboxanes from arachidonic acid associated with gastrointestinal side effects (1). Oral KT is indicated only for the continuation of therapy following initial parenteral administration. Because of its short half-life (4–6 h), KT must be dosed frequently to maintain its therapeutic effect (2). Therefore it may be advantageous to administer sustained-release formulations to reduce side effects and improve patient compliance.  

Previous studies on the risk of gastrointestinal bleeding associated with NSAIDs in animals (3) and in humans (4) proved that bermoprofen and flurbiprofen, respectively, formulated as sustained-release products were effective and well tolerated with fewer gastrointestinal side effects.  

The aim of controlled drug therapy is improved efficiency in treatment—that is, achieving the desired effect and maintaining it for an extended period of time. Objectives of sustained-release formulations include minimizing or eliminating patient compliance problems, minimizing drug accumulation in body tissues with chronic dosing, eliminating either local and systemic side effects, reducing or eliminating drug in blood?level fluctuactions (thereby allowing better disease state management), and improving the bioavailability of some drugs. A potential advantage is that the average cost of treatment over an extended time period may be lower than that of a conventional form (5).   

Many investigators have studied the effect of using various techniques to prolong KT release. Genc and Hegazy reported on the preparation of sustained-release wax matrix formulations of KT with Compritol (6). The authors investigated the effect of cellulose matrices on controlling the release of KT and reported that by mixing the drug with an optimum amount of nonionic hydroxy propylmethylcellulose (HPMC) or methylcellulose and anionic sodium carboxymethyl cellulose polymers, excellent release profiles close to zero order were obtained (7). Vatsaraj et al. prepared KT swelling-controlled matrix tablets using three cellulose derivatives (8). Rokhade et al. reported on the preparation of controlled-release KT microspheres using gelatin and carboxymethyl cellulose sodium (9). 

Eudragit (Rohm Pharma, Darmstadt, Germany) copolymers have been used to prolong KT release in a matrix formulation (10). Eudragit RL and Eudragit RS are insoluble in water and digestive juices. They are capable of swelling, and because of their permeability, the active ingredients are released by diffusion. They are pH-independent, which means that drug release takes place independently of individual variation. Eudragit polymers also have been used by other researchers to prolong the release of diclofenac and ketoprofen (11–13).  

The aim of this study was to prepare sustained-release pellets of KT, that would be given twice per day and that would maintain the effective therapeutic concentration for as long as 12 h. The method would involve a simple microencapsulation technique using Eudragit RL and Eudragit RS and nonpareil seeds as carrier. 

 The following materials were used in this study: KT and propyl gallate (Dr. Reddy's Laboratories, Hyderabad, India); nonpareil seeds, mesh size 18–20 (Mendel, a Penwest company,  Germany); Eudragit RS 100 powder and Eudragit RL/RS 12.5% solution; talc powder (Tardy, Italy); dibutyl phthalate and tetrahydrofuran (Merck, Darmstadt, Germany); methanol and isopropanol (BDH, Poole, England). Other chemicals and reagents were of analytical grade. 

 KT pellets were prepared using nonpareil seeds as an inert carrier. Nonpareil particles were first pan coated (Erweka AR400 apparatebau GmbH, Heusenstamm, Germany) successively with RS 100 solution in isopropyl alcohol (12.5%) until they became visually insoluble in water. KT was then applied onto nonpareil coated pellets in a conventional stainless steel pan using the following formula:   

Eudragit RL/RS, 12.5% solution: 250 parts

Subsequently, the prepared KT pellets were sieved (2 mm) and coated by four coating formulations using various proportions of Eudragit RL and Eudragit RS (see Table I). 

Table I: Composition of the various coating formulations, each containing 5% of ketorolac tromethamine. 

 The flowability of the nonpareil coated seeds was evaluated using the angle of repose method (14). To determine the KT content in the pellets, an accurately weighed amount of pellets containing 10 mg KT was sonicated with 100 mL of methanol for 30 min. The dispersion was then filtered, 5 mL of the filtrate was diluted with 50 mL methanol, and KT content was determined using UV spectrophotometry at 323 nm.  

 26 (15), the mobile phase was a degassed mixture of methanol, water, and glacial acetic acid (55:44:1), with a flow rate of 1.2 mL/min. The high-performance liquid chromatography (HPLC) system (C-R7A pluschromatopac, Shimadzu, Kyoto, Japan) was fitted with a column (250 X 4.6 mm, 5-μm particle size) and a 254-nm detector. 

  Drug release from prepared pellets was assessed using the 

 26 dissolution apparatus, Type I. Appoximately 337 mg of coated pellets were placed in 750 mL of phosphate buffer pH 6.8 as the dissolution medium. The temperature was maintained at 37 ± 0.5 °C and agitated at a rate of 90 rpm. At time intervals 1, 2, 3, 4, 5, 6, 7, 8, and 12 h, samples were withdrawn, filtered, suitably diluted, and the drug concentration was determined with spectrophotometry at 323 nm.  

 The release of KT was fitted to different release models to identify the mechanism of release kinetics from the prepared pellets. 

 The prepared pellets were stored at various conditions; namely, 40 °C and 75% RH; and 30 °C and 75% RH for 4 months; and at shelf conditions (25 °C and  60% RH) for 7 months. 

The effect of the polymer composition used in coating the drug-loaded beads; namely Eudragit RL:Eudragit RS (1:2 and 1:3, respectively) on KT dissolution is shown in Figure 1. Generally, the observed drug release from the coated beads can be arranged according to the following increasing order: Eudragit RS < Eudragit RL:Eudragit RS, 1:3 < Eudragit RL:Eudragit RS, 1:2 < Eudragit RL. The authors observed a reduction of release from 88% in pellets coated with Eudragit RL to only 50% release in pellets coated with Eudragit RS after 2 h of dissolution. Corresponding values were 58.9% and 66.3% for pellets coated with a blend of Eudragit RL:Eudragit RS (1:3 and 1:2, respectively) (see Figure 1).  

Figure 1: Dissolution-rate profiles of ketorolac tromethamine sustained-released formulations (formulations IâIV). (ALL FIGURES ARE COURTESY OF THE AUTHORS.) 

The observed release pattern from different pellets can be attributed to polymer permeability. The relatively higher permeability of Eudragit RL (16) to the dissolution medium could be considered responsible for the observed fast release of KT from the pellet coated only with Eudragit RL (see Figure 1). Including Eudragit RS, which is known to be of lower permeability (16), in the coat composition (Eudragit RL:Eudragit RS = 1:2) led to a reduction in drug release. Increasing the proportion of the less-permeable polymer Eudragit RS in the coating blend to 1:3 (Eudragit RL:Eudragit RS, respectively) resulted in a further reduction in drug release as a result of hindered permeation of the dissolution medium. This effect is most pronounced when the coat is made totally of Eudragit RS, where maximum retardation of drug release is observed (see Figure 1). Drug-release profiles also depend to a great extent on the integrity of the film surrounding the pellets, which is affected by the presence of plasticizer in the coating dispersion (17).   

It seems from the present results that Formula III (Eudragit RL:Eudragit RS = 1:3) is of appropriate drug release such that the release of KT is extended over the test period in addition to a 100% release after 12 h. Although formula II and formula IV had similar release pattern, they showed only 92% and 86% release after 12 h. Therefore formula III was selected for the release kinetics study.  

The release data from the selected pellets (Formula III) coated with Eudragit RL:Eudragit RS (1:3) were fitted to various release models (zero order, first order, and Higuchi models). Table II summarizes the correlation coefficients of these models. A plot of %-KT released over time (see Figure 1) indicated a nonlinear correlation, thereby suggesting that the release pattern from pellets doesn't follow the zero-order kinetic model. Drug release from Eudragit-coated pellets is expected to follow a diffusion-controlled model in accordance with the Higuchi equation (18).  

Table II: The correlation coefficients and release rate constants of ketorolac tromethamine observed for zero-order, first-order, and Higuchi equation. 

The plot of the amount of KT released from pellets versus the square-root of time indicated that the amount of drug released increased linearly (

 = 0.981) with the square-root of time. However, both the square-root of time and first-order release plot were linear, as indicated by the correlation coefficients derived from first-order and Higuchi equations (see Table II). The first-order release curve, however, showed biphasic release profiles with two distinct regions, in agreement with previous reports (19). The first region in the release occurs at a relatively fast rate (0.461 h

), and a terminal region in which a reduction in drug release is observed (0.345 h

) (see Table II). However, the Higuchi equation yielded a correlation coefficient value almost similar to that of the first-order equation (see Table II). 

To further distinguish the exact mechanism of release, the differential form was performed. For a diffusion-controlled mechanism, the rate will be inversely proportional to the total amount of drug released 

 is the rate constant calculated from Higuchi equation, 

is the amount of drug released. The plot of release rate (

 = 0.994), indicating that the release of KT from the pellets was governed by the Higuchi square-root of time kinetics equation. 

It could, therefore, be concluded that the apparent release of KT from the prepared pellets coated with Eudragit RL:Eudragit RS 1:3 appears to follow both diffusion-controlled and first-order kinetics. However, differential rate treatment confirmed that release was governed by a diffusion-controlled mechanism. 

 The selected formulation III was subjected to a stability study by monitoring both its physical and chemical stability of KT. Storage of the product at 25 and 30 °C didn't result in appreciable changes in the physical properties of the tested product regarding color, flow properties, and moisture content. Storage at 40 °C resulted in a color change from white to yellowish white and ending with dark yellow pellets after three months of storage. The discoloration may be attributed to a Maillard reaction of the free amino groups of tromethamine with trace reducing sugars arising from the sugar-based nonpareil seeds. Similar drug and excipient interactions have been reported bewteen amine drugs and carbonyl groups in many pharmaceutical excipients; for example, the interaction of metoclopramide and lactose (20) and vigabatrin and povidone (21), resulting in discoloration in the solid state. Because the discoloration in the present study was observed at an elevated temperature and humidity, it could be postulated that small molecular-weight residuals reducing mono or disaccharides may migrate through the initial Eudgragit RS film, the integrity of which may be compromised under such storage conditions, and finally interact with KT.  

The freshly prepared particles exhibited excellent flow, resulting in angle of repose values <25°. Furthermore, a negative effect was observed on the flow properties of aged pellets, which could be attributed to the elevation of moisture content from 2.29% to 2.99% after two months, with an observed sticking tendency between pellets. Four-months storage at 40 °C and 75% RH led to the formation of cohesive particles, rendering the flow determination impossible. Particles stored at 30 °C and 75% RH showed an angle of repose between 25 and 30°. Storing pellets at shelf conditions (25 °C and 60% RH) maintained the aforementioned physical parameters and resulted in white flowable pellets with almost constant moisture content. 

Concerning the chemical integrity of KT in the prepared pellets, storage under the studied conditions did not affect the drug content. The observed values for KT content after two months were 97.3, 96.9, and 97.6% relative to the fresh pellets after storage at 25, 30, and 40 °C, respectively. 

 The dissolution profiles of the fresh and stored pellets were determined (see Figure 2). Storing the pellets at the worst conditions (40 °C and 75% RH) resulted in an appreciable acceleration in drug release, and 100% drug release was attained after six hours. The enhanced release could be attributed to the elevated moisture content of the pellets (from 2.29 to 2.99 after two months), with an expected adverse effect on the integrity of the Eudragit coat. Moreover, the elevated moisture content may cause the drug to diffuse more easily through the polymer film toward the outer layers and consequently facilitate its release. This assumption may be substantiated by the higher release rate from these pellets, particularly during the initial study hours (see Figure 2). Storage of pellets at 30 °C and 75% RH did not significantly change the release characteristics of fresh pellets. 

Figure 2: Effect of storage conditions on drug release from ketorolac tromethamine sustained-released formulation III. (ALL FIGURES ARE COURTESY OF THE AUTHORS.) 

The release pattern is much better for pellets stored on the shelf, where an almost identical dissolution behavior to zero-time dissolution was observed after seven months of storage (see Figure 2). It could therefore be concluded that conditions of elevated temperature and humidity (40 °C and 75% RH) should be avoided. Moreover, pellets are recommended to be stored at conditions not exceeding 25 °C and 60% RH to maintain a proper extended release over 12 h.  

The proposed formulation (formulation III) provided sustained KT release over 12 h and exhibited good physical and chemical stability. The pellets are recommended to be stored at conditions not exceeding 25 °C and 60% RH to maintain a proper extended-release profile. The recommended formulation will be further tested for 

 is a professor of pharmaceutics at the Faculty of Pharmacy, Alexandria University, Alexandria, Egypt. 

 is the R&D manager at the European Egyptian Company for Pharmaceuticals, Alexandria, Egypt. 

 is an associate professor and chairman at the Department of Pharmaceutics, Faculty of Pharmacy, Kuwait University, PO Box 24923 Safat, 13110 Kuwait, tel. 00965 4986072, fax: 00965 4986843, 

 is a professor at the Faculty of Pharmacy, Alexandria University. 

 is a professor and consultant at Arab Company for Drug Industries and Medical Appliances (ACDIMA), Cairo, Egypt. 

 *To whom all correspondence should be addressed. 

Submitted: March 9, 2008. Accepted: May 23, 2008. 

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 (United States Pharmacopeial Convention Inc., 17th ed., Rockville, MD, 1997), p. 1788.  

 (Thomson PDR, 57th ed., Montvale, NJ, 2003), p. 2942.  

 3.  M. Mori et al., "Prolongation of Antipyretic Action and Reduction of Gastric Ulcerogenicity in the Rat by Controlled-Release Granules of Bermoprofen, a New Nonsteroidal Anti-Inflammatory Drug," 

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The authors evaluated the effect of polymer composition on the drug-release profile and the effect of storage conditions on dissolution characteristics.