Introduction •  L-BPA, or boronophenyl alanine, has therapeutic potential in Boron Neutron Capture Therapy (BNCT) for treatment of glioma via parenteral delivery.

•  A high dose requirement (around 300mg/kg), with a relatively low BPA solubility in fructose (33mg/mL), means a large volume for patient dosing using the current ‘standard’ fructose formulation [1,2] In addition, risk of patient hypersensitivity to fructose contributed to our consideration that the pre-existing BPA formulation was potentially sub optimal [3].

•  At the Formulation Unit, we have developed a novel Phase I clinical trial formulation of L-BPA in 110mg/mL mannitol, increasing drug solubility to 100mg/mL and enabling complete substitution of the fructose excipient. For product stability and shelf life, vial lyophilisation was required. •  Drying from 21% w/w solids, although challenging, was successful, but initial batch production runs have required 6 days of drier time. Reduction of this lengthy drying cycle was sought. For this purpose , SMART© lyophi l i sa t ion technology was to be investigated. Materials and Equipment L-BPA was commercially synthesised for clinical trial use by Syntagon AB, Sweden, and supplied by Hammercap. All other materials were of Pharmacopoeial grade. The clinical batch lyophiliser was a Telstar Liogamma 20/5 Freeze Drier supplied by Freestead Process Technology UK Limited. SMART© lyophilisation technology is commercially available from FTS systems, USA. The Formulation Unit runs this software on a Lyostar II pilot scale tray drier purchased from Biopharma Process Systems, Winchester, UK. Methods •  21 x 50mL Type 1 clear glass vials of internal diameter 37mm (surface area 10.75cm2) were filled to 10mL volume with 100mg/mL BPA in 110mg/mL mannitol, pH8.

Results and Discussion (continued) Figure 3 shows the non ideal drying behaviour of the BPA product. Despite an initial and briefly sharply rising resistance, this does not continue throughout drying: the observation is more of plateau initially, followed by downward trend. Certainly, the relatively high fill depth (0.93cm), and the highly concentrated solute combined may present a barrier to water vapour removal during drying. The final product has a cracked and slightly shrunken appearance. As cracks appear in this particular product, improved vapour flow may result. However, the shrunken cake appearance may indicate some product micro-collapse, corroborated by the decreasing trend in resistance indicating a decrease in resistance to product vapour flow [4]. Conclusion •  Application of SMART© drying to the BPA product gives the possibility of significant cycle reduction, drying a test batch in around 60 hours with a more aggressive selection of the main primary drying temperature around -20°C. Extended studies would be required to determine product stability effects. Acknowledgements Cancer Research UK sponsored this work. The authors acknowledge the invaluable assistance of Drs. Hayley Farmer, Alexandra King and Nigel Westwood (Cancer Research UK Drug Development Office). References [1] J. A. Barth, M. G. H. Vicente Coderre and T. E. Blue, “Boron neutron capture therapy: Current status and future prospects,” Clin. Cancer Res., 11 (2005) 3987-4002 [2] Y. Mori, A. Suzuki, K. Yoshino and H. Kakihana, “Complex-Formation of P- B o r o n o p h e n y l a l a n i n e w i t h s o m e monosaccharides,” Pigment Cell Research, 2 (1989) 273-277. [3] J. Collins, “Metabolic Disease - Time for Fructose Solutions to Go,” Lancet, 341 (1993) 600. [4] H. Giesler, T. Kramer and M. .J Pikal, “Use of manometric temperature measurement (MTM) and SMART™ f reeze dryer technology for development of an optimized freeze-drying cycle,” J. Pharm. Sci, 96 (2007) 3402-3418.

BPA 1g

Mannitol 1.104g 5M NaOH 1.25mL

2M HCl q.s Water for Irrigation To 10mL

Table 1 L-BPA vial formula

Comparison of lyophilisation cycles for a BNCT agent using ‘traditional’ and ‘SMART©’ drying

M. A. Elliott, E. Schmidt, S. J. Ford, L.J. Dick and G. W. Halbert

Cancer Research UK Formulation Unit, Strathclyde Institute for Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow, G4 0RE

Figure 1 Drying program for traditionally dried batches

Figure 2 Drying program for SMART© dried batch

Figure 3 Product resistance versus time (and increasing dry layer thickness)

Methods (continued) •  Filled vials were placed in a ‘nested’ formation on a single tray accommodating 78 x 50mL vials (6 in a row x 13 rows). Empty vials surrounded the test vials.

•  Critical temperature was -35°C. Drying was allowed to proceed under SMART© control.

Results and Discussion One test run using SMART© produced a significant shortening of the cycle time. Selected run parameters were examined and reported graphically in Figure 2 showing the final run concluding before 60 hours.