An assessment of beclomethasone dipropionate clathrate formation in a model suspension metered dose inhaler
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
References (23)
- et al.
Calibration of AFM cantilever spring constants
Ultramicroscopy
(2003) - et al.
Ab-initio structure determination of LiSbWO6 by X-ray powder diffraction
Mater. Res. Bull.
(1988) - et al.
Surfactant promoted crystal growth of micronized methylprednisolone in trichloromonofluoromethane
Int. J. Pharm.
(1994) - et al.
Analytical techniques for quantification of amorphous/crystalline phases in pharmaceutical solids
J. Pharm. Sci.
(2006) The influence of formulation variables on the performance of alternative propellant-driven metered dose inhalers
Adv. Drug Deliv. Rev.
(2003)- et al.
Drug–surfactant–propellant interactions in HFA-formulations
Int. J. Pharm.
(1999) Clathrate hydrates
Annu. Rev. Earth Planet. Sci.
(2000)- et al.
Characterization of drug particle surface energetics and young's modulus by atomic force microscopy and inverse gas chromatography
Pharm. Res.
(2005) - et al.
Structure of the asthma drug beclomethasone dipropionate
Acta Crystallogr. B: Struct. Sci.
(1981) Clathrate hydrates
Ind. Eng. Chem. Res.
(1993)
The significance of molecular type, shape and complementarity in clathrate inclusion
Topics Curr. Chem.
Cited by (11)
Humidity affects the morphology of particles emitted from beclomethasone dipropionate pressurized metered dose inhalers
2017, International Journal of PharmaceuticsCitation Excerpt :Similar findings were reported in work by Lewis, Haghi, and colleagues (Haghi et al., 2014; Lewis et al., 2014). Further studies with BDP solution pMDIs (Buttini et al., 2014) and with model propellant systems (Bouhroum et al., 2010; Ooi et al., 2014) indicate that BDP may form solvates or clathrates with ethanol or propellants during drug particle formation. The morphology of a drug particle may alter its fate after deposition in the lungs as well.
Characterisation of dry powder inhaler formulations using atomic force microscopy
2015, International Journal of PharmaceuticsCitation Excerpt :AFM measurements are also valuable for understanding the prevailing forces in pressurised MDIs. Colloidal probe force measurements can be performed within liquid cells, allowing the impact of propellants such as 2H, 3H decafluoropentane or 2H, 3H perfluoropentane (Ashayer et al., 2004; Bouhroum et al., 2010; Rogueda et al., 2011; Traini et al., 2005, 2007) to be assessed. The role and impact of stabilising agents have also been investigated by colloidal probe AFM in several research projects.
The solid-state and morphological characteristics of particles generated from solution-based metered dose inhalers: Influence of ethanol concentration and intrinsic drug properties
2014, Colloids and Surfaces A: Physicochemical and Engineering AspectsCitation Excerpt :The BDP samples all exhibited exothermic peaks of crystallization at ∼120 °C, suggesting the aerosol particles to be amorphous [17]. Melting endothermic peaks were also observed at ∼211 °C, corresponding the melting of the recrystallized samples [11,18,19]. Particles collected from FP formulations also had exothermic regions of crystallization at ∼95 °C with slightly reduced melting points (∼286 °C), indicating their amorphous property.
Isothermal calorimetry: A predictive tool to model drug-propellant interactions in pressurized metered dose systems
2014, International Journal of PharmaceuticsImaging dehydration kinetics of a channel hydrate form of the HIV-1 attachment inhibitor prodrug BMS-663068
2013, Journal of Pharmaceutical SciencesCitation Excerpt :A second region (data not shown) showed the presence of a fine crack at a RH of 60%, which widened with decreasing humidity, again consistent with the AFM data. Microscopy-based techniques such as AFM have been reported in the study of clathrate API crystals38 and for characterizing the morphology of crystalline APIs in relation to their unit cell. For example, Kiang et al.39 solved the crystal structure of an investigational pharmaceutical compound and then used molecular modeling to predict the external morphology of the crystalline form as having thin, plate-like topology with a dominant (0,0,1) face, which was confirmed by AFM and SEM.
Advances in the analysis of steroid hormone drugs in pharmaceuticals and environmental samples (2004-2010)
2011, Journal of Pharmaceutical and Biomedical AnalysisCitation Excerpt :DSC was found more accurate and sensitive than FT-Raman spectroscopy [56]. Beclomethasone dipropionate clathrate formation with trichloromonofluoromethane for being used in a suspension metered dose inhaler was characterized by XRPD, X-ray photoelectron spectroscopy, scanning electron microscopy and DSC [57]. The desolvation of cortisone acetate hydrates and tetrahydrofuran solvate was followed and characterized by XRPD and DSC [58].