Crystal clear benefit for inhalers

Crystalline compounds called clathrates are of interest to MDI formulation scientists as they can increase thermo-dynamic stability of compounds. New research by Abdennour Bouhroum at Nottingham University, co-sponsored by 3M Drug Delivery Systems, illustrates some potential benefits of propellant clathrates in MDI products

Crystalline compounds called clathrates are of interest to MDI formulation scientists as they can increase thermo-dynamic stability of compounds. New research by Abdennour Bouhroum at Nottingham University, co-sponsored by 3M Drug Delivery Systems, illustrates some potential benefits of propellant clathrates in MDI products

Clathrates are crystalline compounds consisting of a lattice of one type of molecule, which hosts a second type of guest molecule within its structure. The guest molecules prevent the collapse of the open framework structure and render it more thermodynamically stable.

The formation of such entities is of particular interest to the formulation scientist, where in situ formation within the medium is known to occur, but the implications for the stability of the formulation are unknown.

Guest molecules in clathrates are packed (in channels and cages) in co-ordination compound frameworks (see Figure 1). When removed from the stabilising medium, clathrates can become thermodynamically unstable and generally tend to dissociate rapidly due to the presence of large empty cavities at the core of the structure.

Suspension metered dose inhalers (MDI) utilise a particulate Active Pharmaceutical Ingredient (API) within a propellant, usually in the presence of additional excipients, such as ethanol and a surfactant. It is well known that a clathrate of beclomethasone dipropionate (BDP) forms when this particular API is suspended in CFC-11. However, little is known about the subsequent interactions of the clathrate within the formulation.

Recent research co-sponsored by 3M Drug Delivery Systems, was conducted at Nottingham University to investigate the physico-chemical properties of the BDP-CFC-11 clathrate crystallised from tricholoromonofluoromethane (CFC-11) to determine its physical interactions in a model suspension pressurised metered-dose inhaler (pMDI) using decafluoropentane as a model propellant.

The BDP-CFC-11 clathrate is a stable entity and thus suitable as a model for the initial investigations.2 The crystals investigated in this study were grown in 0.1% to 3% w/w BDP in CFC-11 at ambient room temperature. The structure of the BDP CFC-11 clathrate was determined using direct methods such as XPS and X-ray powder diffraction. However, the focus of the research revolved around using Atomic Force Microscopy to determine the dispersive surface free energy (SE) and force of adhesion (Fadh) measurements of the BDP CFC-11 clathrate with different pMDI components in the model propellant (decafluoropentane).

Since the solid state chemistry can significantly alter the physical interactions within a suspension formulation, it is crucial to determine the most stable crystalline form in the presence of the propellant."

The crystal growth of anhydrous BDP in CFC-11 was examined. Anhydrous BDP was suspended in CFC-11 in a pressure-resistant vial, shaken for 2 hours and then placed in the fridge for 24 hours, prior to filtration. The crystals investigated in this study were grown in concentration levels varying from 0.1% to 3% w/w BDP in CFC-11. BDP crystallises with a channel structure that allows the insertion of CFC-11 molecules. The structure is held together through hydrogen bonding.3

Spontaneous crystal growth occurs rapidly when anhydrous BDP is dispersed in CFC-11 with the formation of BDP CFC-11 clathrate. The structure of the clathrate was determined using the direct methods of scanning electron microscopy (SEM), X-ray photoelectron spectroscopy (XPS) and X-ray powder diffraction (XR-PD). In addition, the use of atomic force microscopy (AFM) was employed for the determination of the dispersive surface free energy (SE) and the force of adhesion (Fadh) measurements of the BDP CFC-11 clathrate with different pMDI components in model propellant (decafluoropentane).

geometric structure

Anhydrous BDP, when suspended in CFC-11, forms perfect geometric crystals with a well defined hexagonal structure of about 30-70µm in diameter (Fig. 2). This clathrate formation is spontaneous and quite rapid. Both anhydrous BDP and BDP CFC-11 clathrate were analysed using XPS to determine the difference in their surface chemical composition. The main peaks shown on the different scans corresponded to the three atoms oxygen, carbon, and chlorine respectively. These elements constitute the backbone structure of BDP. The scan obtained for BDP CFC-11 clathrate exhibits an additional small peak at 685 eV position which was assigned to the fluorine and hence confirms the formation of the clathrate.

Attenuated Total Reflection infrared spectroscopy was performed on the BDP CFC-11 clathrates to show the presence of fluorine in the crystal obtained (results not shown). The spectra obtained showed a very noticeable peak at a wavenumber of around 1000cm-1. This peak was ascribed to CFC-11 as it has exactly the same number of peaks and occurs at the same wavenumber (Integrated Spectral Database System of Organic Compounds - SBDS).

The results obtained from XPS were used to calculate the atomic percentage of each element and comparisons were made to the theoretical atomic % (see Table 1). The atomic percentage at the surface of the BDP CFC-11 clathrates obtained appears to be quite different from the theoretical atomic percentage calculated for the 1:1 molar ratio of CFC-11 to BDP. It showed a 0.4:1 molar ratio of CFC-11 to BDP.

The DSC and TGA results for 1.67% w/w BDP in CFC-11 clathrates are represented in Figs. 3 and 4 respectively. Anhydrous BDP melts at 212ËšC, which corresponds to the literature values. The magnitude of the endothermic transition seen at about 100ËšC can be slightly variable and is thought to be due to the release of CFC-11 from the tunnels of the clathrate structure. However, a small exothermic peak can be observed just before the endothermic peak at about 99ËšC which can be speculatively assigned to a solid state rearrangement of the BDP CFC-11 clathrate structure, prior to removal of solvent/propellant from the structure (desolvation).

The structural rearrangement of the clathrate may lead to the opening of channels, which could allow easier desolvation of the CFC-11. The complex thermal events around the melting point observed in the DSC curves for the different samples indicate that BDP undergoes significant degradation during melting. The loss of CFC-11 from the clathrate structure is confirmed by the TGA results (Fig. 4) expressed by 14.5% weight loss which corresponds to 0.6:1 molar ratio of CFC-11 to BDP.

It was found that CFC-11 was incorporated at different ratios into the crystal structures obtained at different concentrations of BDP.

The stoichiometric relationship of the clathrate is not clear. An increased molar ratio of CFC-11 to BDP is observed with an increasing concentration ratio of BDP to CFC-11 during the clathrate formation stage. This appears to reach a maximum at a molar ratio of 0.6:1 of CFC-11 to BDP and then decreases as the concentration increases (Fig. 5). It is not clear why this is the case, but it appears to be reproducible."

The measured XR-PD results matched well with the calculated pattern for the BDP CFC-11 clathrate (Fig. 6) and confirmed that the majority of the BDP and CFC-11 had been crystallised into the BDP CFC-11 clathrate. However, very broad peaks can be observed starting from a 2q value of 18.5ËšC. This corresponds to the CFC-11 molecules present in the structure. In the calculated pattern, the software emits the presence of any molecule inside the channels. Characteristic diffraction peaks can be observed at 2q values of 7.2, 8.5, 9.6, 11.2, 13.8, 16.8, 18.5Ëš for BDP CFC-11 clathrate. These peaks can be used to differentiate this clathrate form from other BDP polymorphs.

The dispersive surface free energies for anhydrous BDP (micronised), the CFC-11 clathrate and ball-milled BDP CFC-11 clathrate are 47.5 ± 4.9 mJm-2, 11.27 ± 4.05 mJm-2 and 15.33 ± 1.40 mJm-2 respectively. Force of adhesion results show that BDP CFC-11 clathrates, even after being ball-milled for 2.5 hours, have a lower Fadh compared with micronised anhydrous BDP with different pMDI components (Fig. 7).

The formation of the CFC-11 clathrate appears to be favourable when compared with the anhydrous form, in terms of its potential interactions within a suspension pMDI formulation. This could therefore have significant implications for the future development of HFA formulations with APIs that are prone to the formation of HFA-134 propellant clathrates.4

The formation of a HFA clathrate may be favourable for one API but not for another. Careful choice of propellant may be prudent for such APIs. However, isolation and full characterisation of such HFA clathrates remains challenging.4 To the author's knowledge, this is the first time that a propellant clathrate has been shown to be beneficial in terms a reduction in the Fadh with pMDI components.

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