Developmental Preformulation Studies in the Design of Travoprost Ophthalmic Solution 0.

004% (TRAVATAN)
S. Airy1, R. Beck2, J. Chiou1, H. Dollinger3, O. Gan4, R. Jani4, B. Kabra5, H. Nguyen1, A. Weiner6 1 Preformulations, 2Process Development, 3Project Management, 4Pharmaceutics, 5 Formulation Development, 6Marketing, Alcon Research, Ltd. AAPS 2002 ABSTRACT Developmental Preformulation Studies in the Design of Travoprost Ophthalmic Solution 0.004% (TRAVATAN), S. Airy, R. Beck, J-S. Chiou, H. Dollinger, O. Gan, R. Jani, B. Kabra, H. Nguyen and A. Weiner, Alcon Research Ltd., Fort Worth, TX Purpose: Developing a stable liquid formulation at 0.004% level involves technical challenges. Varieties of instrumental techniques were used in this preformulation study which helped to identify a final commercial prostaglandin product of travoprost. Methods: A rugged reverse-phase semi-gradient HPLC method was developed to assay travoprost in the target range of 0.004% (40 ppm). Peak purity was confirmed by using diode array detection and electrospray ionization liquid chromatography mass spectroscopic (ESI-LCMS) techniques. Resolution of stereoisomers of related travoprost compounds was achieved by a chiral HPLC method. Accelerated thermal stability and soaking studies with ethylene oxide (EtO) and gamma sterilized packaging materials were conducted at 550C to speed up the aging process. Calorimetric studies were performed with the packaging materials to evaluate thermodynamic parameters for possible terminal steam sterilization. Results: The pH rate profile showed that travoprost is most stable at pH 6.0 0.2 and Tris/borate/mannitol was selected as the best buffer system. The estimation of shelf life at 250C from the observed degradation rate (kobs) was determined to be more than two years using Q10-value calculations. An increase in surfactant concentration from 0.0% to 0.5% level increases the solution clarity, solubility and minimizes the loss of travoprost to the packaging materials. Gamma and EtO

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sterilized low-density polyethylene (LDPE) packaging materials were not compatible. No significant change was observed in EtO sterilized Syndiotactic Polypropylene (SPP) material. Simulated conditions in worst case scenarios were used to evaluate the compatibility of travoprost with process and manufacturing transfer line materials. Thermodynamic data obtained from the calorimetric studies, including the second derivative analysis of thermograms, revealed that terminal sterilization in SPP bottles is not viable. Conclusions: Preformulation studies have successfully resulted in the development of travoprost ophthalmic solution 0.004% (TRAVATAN) packaged in a unique SPP bottle and which demonstrates long term thermal and photo stability.