Informatics Publishing Limited

Edula Sravani ¹, M. K. Chaitanya Mannava ², Damandeep Kaur ³, B. R. Annapurna ¹, Ronaq Ali Khan ³, Kuthuru Suresh ³, Sudhir Mittapalli ³, Ashwini Nangia ², B. Dinesh Kumar ¹

Affiliations
1 Centre for Advanced Research for Pre-Clinical Toxicology, Food and Drug Toxicology Research Centre, National Institute of Nutrition (Indian Council of Medical Research), Hyderabad 500 007, IN
2 Crystalin Research Private Limited, Technology Business Incubator, University of Hyderabad Campus, Hyderabad 500 046, IN
3 School of Chemistry, University of Hyderabad, Central University P.O., Prof. C. R. Rao Road, Hyderabad 500 046, IN

Abstract

Temozolomide (TMZ) is a frontline prodrug for the treatment of glioblastoma multiforme (brain cancer) approved by the US-FDA in 1999. A limitation with this otherwise potent and selective DNA alkylating agent is degradation of the prodrug to the inactive product 5-aminoimidazole-4-carboxamide (AIC) by incipient hydrolysis during storage. This transformation not only makes the drug less effective (due to hydrolysis of the active drug), but also causes discoloration from white to pink and tan brown colour (due to AIC contamination), which can make patients anxious and suspicious about the drug efficacy. We solved the stability issue of TMZ by preparing its succinic acid (SA) cocrystal and showed that TMZ-SA is stable for over 6 months in accelerated stability conditions of 40°C, 75% RH, as confirmed by PXRD. TMZ-SA retained its white colour for over 6 months compared to the tan-brown discoloration for TMZ in less than 1 month. Based on the enhanced stability and comparable dissolution profile of TMZ-SA, we now take forward TMZ-SA pharmaceutical cocrystal to stability assessment by HPLC analysis and preclinical bioavailability and bioequivalence with the reference drug. We observed that there were no significant differences in the pharmacokinetic profile of the test cocrystal TMZ-SA compared to standard drug TMZ in Sprague Dawley rats. The bioavailability ratio was found to be in the range 102-109%. Pharmacokinetic parameters such as T_max, C_max, T_1/2, AUC and Ke are slightly superior for TMZ-SA and the toxico-kinetic profile is also better than TMZ. Most significantly, it has been shown that the active drug is released from the hydrogen-bonded cocrystal and was detected in the brain tissue of rats. Thus we report on a pharmaceutical cocrystal complying with the United States Food and Drug Administration guidance on pharmaceutical cocrystals. These results suggest that TMZSA cocrystal with improved physico-chemical properties is bioequivalent and has superior stability compared to the reference drug TMZ and a potential lead for an improved TMZ formulation.

Keywords

Bioavailability, Bioequivalence, Cocrystal, Glioma, Toxico-Kinetic Profile.

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Damandeep Kaur ¹, Lokesh Shandil , Jyotsna Sengupta ²

Affiliations
1 Society for Promotion of IT in Chandigarh (SPIC), Chandigarh, IN
2 Department of Computer Science, Punjabi University, Patiala, IN

Abstract

Campus Grid computing involves heterogeneous resources of an organization working in collaboration to solve the problems that cannot be addressed by a single resource. However, basic problem for Campus Grid users is how to discover the best resources required for the particular type of a job. There are various approaches using which Grid Discovery can be performed. This paper provides the grid resource discovery solutions for Campus Grid using Globus Toolkit which will enable us to customize the resource information according to the requirements based on the jobs to be run on the Campus Grid and present it in our own format. Here we propose building up our own service on top of globus MDS in order to process the information provided by MDS and use it in our Campus Grid Portal.

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