Using a multi-variable design approach this study sought to determine whether calcium polyphosphate (CPP) could be precipitated with a significantly higher chain length than achieved with conventional melt-derived glass and subsequently enhance the performance of the CPP-based drug delivery matrix. Manipulating aqueous sodium polyphosphate concentration, order of reactant addition, and Ca/P molar ratio at mix of reactants across a minimum of two levels was found to significantly influence the chain length, Ca/P ratio, and residual sodium of the resulting CPP precipitates. The various interactions of these three variables were also found to have a significant impact on the aforementioned properties of the precipitates and we successfully fabricated a precipitate with a 6-fold increase in chain length over that achieved by conventional melting. Despite not seeing a significant improvement in drug release properties, our systematic preparation of calcium polyphosphate from aqueous sodium polyphosphate solutions yielded valuable mechanistic data on this interesting fabrication strategy. (C) 2015 Elsevier B.V. All rights reserved.