A freeze-dried injectable form of flurbiprofen: development and optimisation using response surface methodology
Introduction
Non-steroid anti-inflammatory drugs (NSAIDs) are widely utilised for the symptomatic relief of arthritis. Flurbiprofen, 2-fluoro-α-methyl[1,1-biphenyl]4-acetic acid, belongs to this group of therapeutic agents. Flurbiprofen has a low solubility in water and has poor wettability properties. One serious side-effect of this type of drugs is gastrointestinal irritation and many attempts have been made in order to reduce or eliminate this problem. Examples are pro-drug formation, addition of neutralising excipients, microencapsulation or even the simultaneous administration of anti-ulcer drugs (Loftsson et al., 1981; Nixon and Harris, 1986). Parenteral forms have not been successful due to the low solubility properties of these agents.
Cyclodextrins (CDs) are capable of forming inclusion complexes with a variety of drugs. This mechanism is achieved by enclaving either a complete drug molecule or a part of it, into the cavity area (Szejtli, 1990, Loftsson et al., 1991). This molecular encapsulation will affect the physicochemical characteristics of the drug, including aqueous solubility. For this purpose, a number of cyclodextrins have been designed and tested in drug formulations. In the present investigation, one of these derivatives, namely 2-hydroxypropyl-β-cyclodextrin (2-HPβCD) which is tolerated as a parenteral carrier (Szejtli, 1991), was used to form a flurbiprofen complex with increased water solubility. Afterwards, the solution was freeze-dried.
Finally, some characteristics of the product were optimised, in relation to its production and its final specifications, by using response surface methodology (Bolton, 1990).
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Materials and methods
Flurbiprofen USP from Boots (UK) company and 2-HPβCD (MW=1300) from Janssen Biotech (Belgium), were used. Water for injection (WFI), was produced by five times distillation. All other materials used were of analytical grade. The vials were of clear glass tube type I, 20 mm neck from Glaskontor (Germany) and the chlorobutyl rubber stoppers were formulation 4416 grey, purchased from Pharma Gummi (Italy). The vials used had a volume of 5, 13 and 20 ml with internal diameters 1.88, 2.23 and 2.89
Inclusion complexation in solution
The phase solubility data are shown in Fig. 1. The solubility of flurbiprofen is increased linearly as a function of 2-HPβCD concentration and the solubility curve can be generally classified as type AL (Higuchi and Connors, 1965). This indicates that the stoichiometry of the complex is 1:1 (guest:host). The apparent formation constant K1:1 was calculated according to the following equation:where S0 is the intercept of the line.
Applying the data of Fig. 1 to the above
Conclusions
The experimental results indicate that a complex of flurbiprofen and 2-HPβCD was formed, with increased solubility characteristics, which was achieved by the freeze-drying technique. Furthermore, the freeze-dried product was readily soluble in water in such concentrations that the drug could be used in parenteral formulations. Finally, with the use of experimental design techniques, such as response surface methodology, the optimisation of two major characteristics of the product is possible,
References (8)
- et al.
Improved delivery through biological membranes. VIII. Design, synthesis and in vivo testing of true prodrugs of Aspirin
J. Pharm. Sci.
(1981) - Bolton, S., 1990. Optimization in Pharmaceutical Statistics. Marcel Dekker, New York, pp....
- Higuchi, T., Connors, K.A., 1965. Phase solubility techniques. In: Reilley, C.N. (Ed.), Advances in Analytical...
- et al.
A freeze-dried injectable form of Ibuprofen: development and optimisation using response surface methodology
PDA J. Pharm. Sci. Technol.
(1996)