Abstract
The low solubility of recently developed drugs and those still in the pipeline requires appropriate formulation approaches. Common strategies to improve the solubility of drugs include chemical modification of the drug, modification of the vehicle, or physical alteration of drug particles, including size reduction to the micro- or nanometer scale, or altering the solid state form, in particular the use of the amorphous form. The latter has the advantage of a higher apparent solubility but is physically unstable and therefore may recrystallise during storage or application. The focus of this work was on understanding solid state conversions on the surface. This included surface crystallisation and its inhibition via surface coverage and coating, as well as the reverse process of amorphisation at the surface.
The effect of surface crystallisation on quantification of the crystallinity content was investigated using different analytical techniques. Quench cooled indomethacin (IMC) was analysed with Fourier transform attenuated infrared (FT-ATR-IR) spectroscopy, X-ray powder diffraction (XRPD) and differential scanning calorimetry (DSC) during storage. According to FT-ATR-IR spectroscopy (a surface biased technique), crystallisation was completed after 5 days, DSC could not detect any amorphous content after 100 days, and according to XRPD crystallisation was still incomplete after this time. The result for XRPD was believed to be due to its relative insensitivity to small nanocrystals. However, after 5 days of storage the samples showed the same dissolution behaviour as crystalline IMC indicating that FT-ATR-IR could predict dissolution behaviour of surface crystallised samples best. Overall, in this study it was shown that when determining crystallisation behaviour the analytical technique used should be most relevant to the critical quality attribute of interest, in this case, dissolution behaviour.
One possibility to slow down surface crystallisation is covering the particle surface. Compared to other stabilisation mechanisms, such as formation of a glass solution or use of silica, the drug load can be maintained at a higher level. This could potentially be achieved using particle interactions with surfaces as well as films/coats. This particular approach was tested by preparation of quench cooled IMC and either Soluplus® or Eudragit® E as the polymer in physical mixtures of different ratios (3:1, 1:1 and 1:3 (w/w)). While IMC Soluplus® mixtures did not show increased physical stability in either ratio, according to XRPD, IMC Eudragit® E mixtures did. This could be explained with the surface coverage of drug and polymer in the physical mixtures. Due to the small particle size, Eudragit® E particles aggregated around IMC and probably acted as a physical barrier that inhibited crystals growing outwards from the particle and also reduced the molecular mobility on the surface. These mechanisms could slow down surface crystallisation.
To investigate more technologically robust methods of surface coverage with a potential for higher drug loading, quench cooled IMC particles were coated using several approaches including heat coating together with aggregated Eudragit® E particles, coating in a mini fluid bed with Eudragit® E solution, a three fluid nozzle spray drying approach and dipping in polymer solutions. A smooth coat of 10 μm thickness was built up through heat coating, but the IMC recrystallised to the α-polymorph. During the mini fluid bed coating IMC did not recrystallise, but the coat quality was not reproducible. The three fluid nozzle approach resulted in the formation of an IMC Eudragit® E glass solution or solid dispersion. The dipped IMC samples showed a better physical stability compared to pure amorphous indomethacin as detected with XRPD. Polymer type, concentration and dipping time influenced the stabilisation efficiency. Overall, the study showed that coating amorphous particles can inhibit surface crystallisation while maintaining a high drug load.
In addition to recrystallisation, amorphisation at the surface of compacts was also investigated, with an approach termed in situ amorphisation. This study aimed to combine the advantages of crystalline and amorphous material, storage stability and a higher apparent solubility. Tableted mixtures of crystalline IMC and Eudragit® E spontaneously amorphised in situ during dissolution testing at pH 6.8. The amorphous form was confirmed with XRPD, DSC and FT-ATR-IR. When in situ amorphised samples were subjected to further dissolution testing at pH 4.1 they dissolved faster than crystalline IMC Eudragit® E mixtures and comparably to solid solutions. The suggested mechanism is that Eudragit® E particles form a film at pH 6.8 in which some IMC can molecularly dissolve into, and at the pH where the polymer film can dissolve (i.e. pH 4.1) the drug is released. The work showed that in situ amorphisation is a potential formulation approach for poorly water soluble drugs.
Overall this work highlighted the importance of solid state changes at the surface in impacting both crystallinity analysis and the critical quality attribute, dissolution behaviour. The reduction of surface crystallisation could be achieved by coverage of the surface of amorphous particles using different approaches. The possibility of in situ amorphisation during dissolution testing offers an exciting new approach for the formulation of poorly water soluble drugs without physical stability problems.