Physicochemical Investigation of the Influence of Saccharide-Based Parenteral Formulation Excipients on l-p-Boronphenylalanine Solubilisation for Boron Neutron Capture Therapy

Abstract

This paper investigates the physicochemical properties of possible pharmaceutical alternatives to L-p-boronphenylalanine (BPA)-fructose intravenous formulation currently employed in boron neutron capture therapy. The physicochemical properties of BPA in the absence and presence of fructose, mannitol, trehalose and hydroxypropyl-β-cyclodextrin (HPCD) was investigated by determination of pKa values, solubility, precipitation and dissolution using a Sirius T3 instrument. Complex formation was also assessed using (10) B-Nuclear magnetic resonance (NMR). The results indicate that fructose and mannitol form a complex with BPA through a reversible interaction with the boronic acid group, determined by changes in the pKa of the boronic acid group, the ultraviolet and NMR spectra, and increase in kinetic solubility. Trehalose and HPCD did not undergo this reaction and, consequently, did not affect boronphenylalanaine physicochemical properties. Although mannitol is complexed with BPA in an identical manner to fructose, it is superior because it provides increased kinetic solubility. Replacement of fructose by mannitol in the current clinical BPA formulation is, therefore, feasible with advantages of increased dosing and removal of issues related to fructose intolerance and calorific load. Results also indicated that important pharmaceutical parameters are the complex's solubility and dissociation behaviours rather than, as originally assumed, the complex formation reaction.

Interaction of Model Aryl- and Alkyl-Boronic Acids and 1,2-Diols in Aqueous Solution

“…[3][4][5] The solubility of bortezomib in water is about 0.5-0.6 mg/mL, whereas in the presence of 1% mannitol, a solubility of 4 mg/mL has been reported because of ester formation. 4,5 Except for the work of Yan et al, Springsteen and Wang, and a few others, [9][10][11][12][13][14][15][16] relatively limited quantitative information on boronic acid ester formation with 1,2-diols is available. However, the interaction of boronic acid derivatives and sugars has long been used for separation and analytical purposes as well as in designing drug delivery devices, especially those used to sense glucose changes.…”

“…Except for the work of Yan et al, Springsteen and Wang, and a few others, relatively limited quantitative information on boronic acid ester formation with 1,2‐diols is available. However, the interaction of boronic acid derivatives and sugars has long been used for separation and analytical purposes as well as in designing drug delivery devices, especially those used to sense glucose changes.…”

The influence of non-ionisable excipients on precipitation parameters measured using the CheqSol method

“…This property is utilised in the chasing equilibrium solubility or CheqSol approach which relies on pH changes produced by the addition of acid or base, to change the ratio of non‐ionised to ionised drug present and to alternate between supersaturated and subsaturated conditions permitting the determination of both the kinetic and intrinsic solubilities (see Figure a). This technique, which was initially aimed at early drug development and candidate screening studies, should however be applicable to situations where the determination of solubility is required such as parenteral formulation development or crystallisation . Recently, we have employed this technique to determine solubility increases associated with the solubility enhancing excipients hydroxypropyl‐β‐cyclodextrin (HPβCD) and the poloxamers 407 and 188 .…”