Research Articles
Polymer–drug compatibility: A guide to the development of delivery systems for the anticancer agent, ellipticine

https://doi.org/10.1002/jps.10533Get rights and content

Abstract

To establish a method for predicting polymer–drug compatibility as a means to guide formulation development, we carried out physicochemical analyses of polymer–drug pairs and compared the difference in total and partial solubility parameters of polymer and drug. For these studies, we employed a range of biodegradable polymers and the anticancer agent Ellipticine as the model drug. The partial and total solubility parameters for the polymer and drug were calculated using the group contribution method. Drug–polymer pairs with different enthalpy of mixing values were analyzed by physicochemical techniques including X‐ray diffraction and Fourier transform infrared. Polymers identified to be compatible [i.e., polycaprolactone (PCL) and poly‐β‐benzyl‐L‐aspartate (PBLA)] and incompatible [i.e., poly (d,l‐lactide (PLA)], by the above mentioned methods, were used to formulate Ellipticine. Specifically, Ellipticine was loaded into PBLA, PCL, and PLA films using a solvent casting method to produce a local drug formulation; while, polyethylene oxide (PEO)‐b‐polycaprolactone (PCL) and PEO‐b‐poly (d,l‐lactide) (PLA) copolymer micelles were prepared by both dialysis and dry down methods resulting in a formulation for systemic administration. The drug release profiles for all formulations and the drug loading efficiency for the micelle formulations were also measured. In this way, we compared formulation characteristics with predictions from physicochemical analyses and comparison of total and partial solubility parameters. Overall, a good correlation was obtained between drug formulation characteristics and findings from our polymer–drug compatibility studies. Further optimization of the PEO‐b‐PCL micelle formulation for Ellipticine was also performed. © 2004 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 93:132–143, 2004

Section snippets

INTRODUCTION

Compatibility between a drug and polymer is known to be one of the key factors in determining the effectiveness of polymeric delivery systems. Herein we consider compatibility between a polymer and drug to refer to miscibility and/or interaction with no alteration in the chemical structure of the polymer or the drug. Because each drug has its own unique chemical and physical properties, no delivery vehicle prepared from a particular polymer will serve as a universal carrier for all drugs. The

Materials

Ellipticine, polycaprolactone (MW = 14,000), poly (d,l‐lactide) (MW = 75,000–120,000), poly (glycolide) (MW = 100,000–125,000), poly‐β‐benzyl‐L‐aspartate (MW = 11,500) and all solvents (HPLC grade) were purchased from Sigma‐Aldrich Chemical Company (St. Louis, MO). The block copolymers, poly (ethylene oxide)‐b‐polycaprolactone (with MW = 5000 for poly (ethylene oxide) and 4000 for polycaprolactone, i.e., PEO5000b‐PCL4000) and poly (ethylene oxide) b‐poly (d,l‐lactide) (with MW = 5000 for poly

Calculations and Comparison of Solubility Parameters

Table 1 includes the values we obtained for the partial solubility parameters for Ellipticine and various polymers calculated by GCM. The value for the total solubility parameter for Ellipticine (δt = 26.09) was very close to that obtained using Molecular Modeling Pro software (Chem SW Inc.) (data not shown). Thermodynamic criteria for the mutual miscibility of two substances is based on the free energy of mixing (ΔGM); that is, if ΔGM is negative, the two substances are said to be mutually

CONCLUSION

Our studies have shown that consideration of partial solubility parameters and calculation of ΔHM enables prediction of polymer–drug compatibility. The X‐ray analyses of polymer–drug blends clearly provided an indication of which polymer was most suitable for Ellipticine.

The formulation studies including preparation of homopolymer films and copolymer micelles, demonstrated that consideration of solubility parameters and physico‐chemical analyses may be used to choose a suitable polymer for a

Acknowledgements

The authors would like to thank Professor R. MacGregor for allowing J. Liu to use his fluorometer, Professor E. Kumacheva for allowing J. Liu to use dynamic light scattering instrument. The authors are also grateful to NSERC and the University of Toronto Rosenstadt Fund for funding this research.

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