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
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 in vivo performance.
Mohamed Etman is a professor of pharmaceutics at the Faculty of Pharmacy, Alexandria University, Alexandria, Egypt. Hala Nada is the R&D manager at the European Egyptian Company for Pharmaceuticals, Alexandria, Egypt. 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, firstname.lastname@example.org
. Fatma Ismail is a professor at the Faculty of Pharmacy, Alexandria University. Mamdouh Moustafa is a professor and consultant at Arab Company for Drug Industries and Medical Appliances (ACDIMA), Cairo, Egypt. Said Khalil is a professor at the Faculty of Pharmacy, Alexandria University.
*To whom all correspondence should be addressed.
Submitted: March 9, 2008. Accepted: May 23, 2008.
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