Development and evaluation of ticlopidine HCI tablets

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Date
2006
Authors
Raj Singh, Thakur Raghu
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Abstract
Ticlopidine HCI is a platelet aggregation inhibitor, which is widely used in the treatment of platelet-dependent disorders, such as cerebral vascular disease, ischemic heart disease and peripheral vascular disease. Ticlopidine HCI products have been reported to be unstable which could be attributed to the type of disintegrant used in the formulation. As such, in the development of Ticlopidine HCI tablets using commonly used disintegrants, .namely, croscarmellose sodium, sodium starch glycolate, crospovidone (XL and XL-10) and cornstarch, the physical stability was evaluated under stress conditions. It was noted that the physical properties of ticlopidine HCI tablets containing croscarmellose sodium, sodium starch glycolate and crospovidone (XL and XL- 1 0) changed on storage but tablets containing cornstarch were stable after storage at 40°C/75%RH for 6 months. Cornstarch was selected as disintegrant in the preparation of ticlopidine HCI tablets. The amount and the mode of incorporation of cornstarch (intragranular or distributed between intragranular and extragranular phases) were varied to achieve in vitro release profile as closely similar as possible to that of the reference product, Ticlid®. A univariate ANOVA method and fit factors (difference factor and similarity factor) were used for dissolution profile comparisons. The dissolution profile of formulation F6 (containing 9% cornstarch with 6% added intragranularly and 3% extragranularly) was found to be similar to that of Ticlid®. The fit factors were found to be more superior than the univariate ANOVA method. F6 tablets were stable in physical and chemical properties after 6-month storage at 40°C/75%RH and the estimated shelf-life was 65.8 months, which could be further extended by protecting the tablets in a suitable package. Prior to the in vivo study, a simple, specific and sensitive HPLC method with UV detection was developed and validated for the quantification of ticlopidine in rabbit plasma. The in vivo performance of the final formulation, Formulation F6, was evaluated by conducting bioavailability and bleeding t1me studies in comparison with Ticlid® using twelve healthy white New Zealand female rabbits in a randomized, two-way crossover design. The rate and extent of absorption as well as the bleeding time of Formulation F6 were fo~nd to be comparable with Ticlid®. In addition, the time required to achieve the maximum bleeding time corresponded to that of T max values for both preparations. In conclusion, a stable generic ticlopidine HCI tablet preparation containing cornstarch as disintegrant demonstrating similar in vitro dissolution profile and in vivo performance as that of Ticlid® was successfully developed.
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Ticlopidine HCI tablets
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