An assessment of beclomethasone dipropionate clathrate formation in a model suspension metered dose inhaler

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Abstract

The aims of this study were to investigate and characterize the physico-chemical properties of beclomethasone dipropionate (BDP) crystallized from tricholoromonofluoromethane (CFC-11). Physical interactions in a model pressurised metered dose inhaler (pMDI) system and changes in surface energy after size reduction (micronization) were determined. Although CFC-11 has largely been phased out of use in pMDIs due to its ozone depletion potential, the BDP CFC-11 clathrate is a stable entity and thus suitable as a model for our initial investigations. In addition, although propellant clathrates have been known for sometime, as far as the authors are aware, their surface energies and adhesive interactions have not been reported. The structure of the clathrate was investigated using scanning electron microscopy (SEM), X-ray photoelectron spectroscopy (XPS) and X-ray powder diffraction (X-RPD). In addition, atomic force microscopy (AFM) was employed to determine the dispersive surface free energy (SE) and force of adhesion (Fadh) of the BDP CFC-11 clathrate with different pMDI components in a model propellant (decafluoropentane).

The dispersive surface free energies for anhydrous BDP (micronized), the CFC-11 clathrate and ball-milled BDP CFC-11 clathrate are (47.5 ± 4.9) mJ m−2, (11.3 ± 4.1) mJ m−2 and (15.2 ± 1.3) mJ m−2 respectively. Force of adhesion results shows that BDP CFC-11 clathrates, even after being ball-milled for 2.5 h, have a lower Fadh compared to micronized anhydrous BDP with different pMDI components. This shows that the formation of the crystalline CFC-11 clathrate is advantageous when compared to the micronized anhydrous form, in terms of its surface energy and potential interactions within a suspension MDI formulation. In the wider context, this work has implications for the future development of HFA formulations with APIs which are prone to the formation of propellant clathrates.

Introduction

The replacement of chlorofluorocarbon (CFC) with hydrofluoroalkane (HFA) propellants has challenged formulators of pressurised metered dose inhalers (pMDIs) in several major aspects. Due to the increased polarity of HFA, the use of alternative (soluble) surfactants or co-solvents, along with traditional surfactants, is required in order to stabilize pressurised suspension products. The surfactant type and composition, as well as drug concentration and particle size, may have an effect on the solubility of an active pharmaceutical ingredient (API), and any related crystal growth could affect the efficacy of a formulation (Smyth, 2003).

Clathrates are a class of inclusion compounds, which generally consist of two molecular species. These arrange themselves in space, so that one molecule (host) entraps the other (guest) (Englezos, 1993) in polyhedral cavities (Koh, 2002). Guest molecules can fully occupy (bonded to the host network) or partially occupy (occupying void spaces) the cages in the host framework (Patchkovskii and Tse, 2003). The thermodynamic stability of the clathrate depends strongly on the size and shape of the guest molecules which must be small enough to fit into the cavities of the lattice, but large enough to lend stability to the structure (Buffett, 2000).

Spontaneous crystal growth occurs rapidly when anhydrous BDP is dispersed in CFC-11 with the formation of the BDP CFC-11 clathrate. The structure is stabilized through hydrogen bonding. Since solid state chemistry can significantly alter the physical interactions within a suspension formulation, it is important to determine the most stable crystalline forms of BDP in the presence of the propellant.

The aims of this study were to investigate and characterize the physico-chemical properties of beclomethasone dipropionate (BDP) crystallized from tricholoromonofluoromethane (CFC-11). Physical interactions in a model pressurised metered dose inhaler (pMDI) system and the effect of size reduction (ball-milling) on surface energy was also determined.

Section snippets

Materials and sample preparation

Anhydrous BDP (micronized) was purchased from Sicor (UK); 1,1,2-tetrafluoroethane (HFA 134a) was supplied by Dupont (UK) and CFC-11 was supplied by Arkerma (UK). All other chemicals were purchased from Sigma–Aldrich Company Ltd. (UK), unless otherwise indicated. 3 M Drug Delivery Systems (UK) supplied a micronized isopropyl alcohol (IPA) clathrate of BDP for investigation (EP 205530).

Morphological comparison between BDP CFC-11 clathrates and BDP EtOH HFA-134a clathrates

The BDP CFC-11 clathrates showed a rapid growth of the crystals. SEM images of the particles are shown in Fig. 1A. The micrographs obtained with BDP CFC-11 indicate the formation of well-defined crystals with hexagonal morphology. The crystals are poly-dispersed, with a size range of 30–70 μm.

An SEM image of crystals obtained from BDP in HFA-134 and ethanol is shown in Fig. 1B. Crystalline particles smaller than the BDP CFC-11 clathrate are observed. The particles are mostly aggregated into

Conclusions

In conclusion, a BDP CFC-11 clathrate has been synthesized and characterized in order to investigate the potential benefits of clathrate formation in metered dose inhaler formulations. The release of CFC-11 from the clathrate form of the steroid was due to a structural rearrangement of the clathrate.

Surface roughness values for each solid form were determined at sample sizes of 5 μm × 5 μm. The different BDP entities ranked in terms of surface roughness as follow: anhydrous BDP > ball-milled BDP IPA

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