hi saeideh

Hydrochloric acid salts of p-BPA have been used to increase p-BPA solubility (See e.g., Ichihashi et al., J. Invest. Dermatol. 78: 215 [1982]; Yoshino et al., Proc. 2nd International Symp. on Neutron Capture Therapy, p. 291 [1986]). However, the acidity imparted by hydrochloric acid salts of p-BPA (e.g., a 0.1 M solution is reported to have a pH value of approximately 1.5), causes pain to patients injected with p-BPA solution of this acidity (Mori et al., supra; Yoshino et al., Strantenthen Onkol. 165: 127-129 [1989]). Therefore, it is desirable to find methods of increasing the solubility of p-BPA at physiological pH.

One method for increasing p-BPA solubility is the use of organic complexes. Complex formation of boric acid, borate and aromatic boronic acids with different polyols has been known for some time (See e.g., Kuivila et al., J. Org. Chem. 19: 780 [1954]; Lorand et al., J. Org. Chem. 24: 769 [1959]; Aronoff et al., Carbohydrate Res. 40: 299-309 [1975]; van Duin et al., Tetrahedron 40: 2901-2911 [1984]; van Duin et al., Tetrahedron 41: 3411-3421 [1985]; Shinkai et al., J. Chem. Soc., Chem. Commun., pp. 1039-1041 [1991]; Verchere et al., Polyhedron 6: 1415-1420 [1987]; Kondo et al., Tetrahedron 48: 8239-8252 [1992]; Shiomi et al., J. Chem. Soc. Perkin Trans., pp. 2111-2117 [1993]; Tsukagoshi et al., J. Org. Chem. 56: 4089-4091 [1991]; James et al., Angew. Chem. Int. Ed. Engl. 35: 1910-1922 [1996]; Wood et al., Carbohydrate Res. 36: 247-256 [1974]; James et al., J. Chem. Soc., Chem. Commun., pp. 477-478 [1994]; Kinoshita et al., in Progress in Neutron Capture Therapy for Cancer, pp. 243-246, Allen et al., eds., Plenum Press, New York [1992]). The solubility effects of monosaccharides and polyols allow for more efficient intravenous use of p-BPA (See e.g., Mori et al., supra; U.S. Pat. No. 5,492,900, supra; Honda et al., in Progress in Neutron Capture Therapy for Cancer, Allen et al., eds., Plenum Press, page 421 [1992]; Mishima et al., in Progress in Neutron Capture Therapy for Cancer, Allen et al. (eds.), Plenum Press, page 577 [1992]; Matalka et al., Cancer Res. 53: 3308 [1993]). For example, studies have shown that systemic administration of p-BPA-fructose complex increases the 10B uptake in a murine melanoma model (Coderre et al., Int. J. Radiation Oncology Biol. Phys. 30: 643-652 [1994]).

Furthermore, p-BPA exists in different forms at different pH values, and complexing of p-BPA with monosaccharides is a pH dependent process. Recent studies have reported a method of solubilizing p-BPA at neutral pH using fructose, to yield a p-BPA-fructose complex (See, Mori et al., supra; U.S. Pat. No. 5,492,900, supra). These methods involve mixing equimolar amounts of p-BPA and fructose in water, increasing the pH to about 10 to dissolve all solids, and subsequent pH adjustment to 7.4 using a concentrated acid (i.e., hydrochloric acid). However, the current methods produce roughly one equivalent of NaCl (depending on how high the pH is raised), thus greatly exceeding its iso-osmotic point with blood and may be partially responsible for the toxicity observed when administered intravenously (LaHann et al., in Advances in Neutron Capture Therapy, Soloway et al., eds. Plenum Press, page 513 [1993]). Additionally, the solution must be used within two days of its preparation and requires a trained technician working with concentrated solutions of HCl and NaOH in an aseptic laboratory environment in close proximity to the treatment area.

Thus, it is desirable to find methods of making p-BPA complexes that are free of NaCl salts. Additionally, by understanding the chemical nature of the complex of p-BPA with fructose, other new complexes may be discovered. It is also desirable to find new p-BPA complexes that can be stored for a long time, and that eliminate the need for working with concentrated acids and bases.

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