Continuous granulations and the particle morphology
The final optimised processing temperature of the extruded granules was set at 180 °C, as previously, this temperature was found most appropriate in order to process and obtain amorphous granules . The unique formulation compositions and the drug/carrier miscibility produced a completely homogenous system in a free-flowing granulated forms. This could be attributed to the high flowability (Carr’s index above 10) of US2 that contains Al2O3 (~ 30%) enabling it to adsorb the BMA molecules and thus dry up the whole system and eventually evacuate the extrudates in free-flowing powder forms . It has been reported that the tetrahedron or octahedron-shaped Al2O3 forms a complex three-dimensional structure in US2 making the compound an excellent proton donor or acceptor . As a result, US2 facilitates a completely dry blending process in extrusion which can add a new insight for pharmaceutical research and development when TSG is involved by eliminating any further down streaming processing steps. Whilst the down streaming processing during a typical HME is considered as one of the major drawbacks, can perhaps, be remarkably absent in foregoing process making this innovative idea to enjoy a resurgence in the future formulation strategy when US2 is used as a novel carrier excipient.
The surface morphology of the produced granules examined via SEM showed no drug crystals on the extrudate surface. Rather, it showed agglomerated granules in irregular shapes. There was also no evidence of the different phases in any of the granules which could be attributed to the intensive high shear mixing during the processing. Also, this could be related to the drug entrapment into the meso-porous US2 network with high specific surface area (300 m2 g−1) during the processing. Interestingly, at a very high resolution, the particle size has dramatically fallen into nanoscale (Fig. 1) and the granules are more agglomerates of nano-sized particles. This foregoing phenomenon can eventually be of great interests in oral drug delivery systems and thus opening a new scope of utilising nano-technology via TSG approach.
Reverse optical microscopy examined the surface morphology of the granulated particles. As can be seen in Fig. 2, the fluorescent particles of US2 present in the formulations are spherical and porous. There are some particles adsorbed on the surface of fluorescent spherical particles which could be the drug particles. These images also show the homogeneous distribution and uniformity of drugs within the carrier matrices in all of the formulations. In general, at a molecular level, absorbance relates to energy status of the particles and their ability to excite the electrons within their orbital. As a result, it is seen that the US2 particles are porous, and BMA molecules may have been adsorbed or entrapped within the porous structure of US2.
The particle size distribution and d10, d50 and d90 values were determined for all extruded granules. As depicted in Fig. 3, data obtained from the analysis showed the particle sizes lower than 115 μm for all formulations which is quite similar to that of US2 (d90 130 μm). In contrast, the bulk BMA showed very fine particles with a narrow mono-modal distribution and d90 22 μm. A small percentage can be seen at sizes > 300 μm due to some agglomerates produced during the granulation process. Nevertheless, all extruded granules were within the range suitable for the oral solid dosage forms and showed excellent flow properties.
Solid state analysis
The solid state of the bulk compounds, physical mixtures (PM) and the extruded granulated formations were examined via DSC. The DSC thermograms of bulk BMA showed sharp melting transitions at ~ 162.1 °C with a fusion enthalpy (ΔH) of about ~ 101.1 J g−1 (Fig. 4). The analysis of the combined heat flow of the bulk MAS showed no crystalline melting endotherms indicating its amorphous nature [25, 26]. All drug–carrier physical mixtures exhibited sharp melting transitions at slightly shifted towards lower temperature in the range of 150–155 °C corresponding to the melting of the crystalline BMA. The heat of fusion increased with the increase of the drug content in the formulations. For example, US2 4 (20% BMA) showed an enthalpy (ΔH) of ~ 11 J g−1, whereas US2 1 (50% drug) showed ΔH of about ~ 29 J g−1 which is in line with the theoretical calculations. In contrast, there were no endotherms observed in any of the extruded granules. The absence of melting transitions corresponding to BMA in all of the formulations indicates the absence of the crystalline BMA and thus the development of amorphous system . Moreover, the absence of multiple Tgs in the formulations indicates that the drug is entrapped within the porous network of the inorganic carrier US2, as the Tg of the US2 is well above the temperature range used in this study (~ > 300 °C). Nonetheless, it can be claimed that the US2 can successfully be used as a novel inorganic carrier to manufacture amorphous drug-containing granulated formulations.
Furthermore, the US2-based extruded granules, bulk drug and the corresponding physical mixtures of the same compositions were studied by X-ray analysis in order to examine the crystallinity of the drug in the formulations. All diffractograms were recorded to examine BMA crystalline state. As can be seen in Fig. 5, the diffractogram of bulk BMA showed distinct characteristic intense peaks at various 2θ positions indicating that the BMA is highly crystalline. Similarly, the physical mixtures of all BMA formulations showed identical but low intense peaks suggesting that the drug retains its crystallinity in the physical blends. In contrast, no distinct intensity peaks were observed in the diffractograms of the extruded formulations even at high drug loadings e.g. in US2 1 with 50% w/w drug. The absence of BMA intensity peaks indicates the presence of its amorphous state or molecularly dispersed state into the US2 matrices after the granulation process was optimised. The results obtained in the XRPD complement the findings from DSC analysis.
The drug BMA contains both phenyl carbonyl and carboxylic acid groups in the structure (Fig. 6) [12, 26]. The FTIR spectra of the crystalline BMA showed the acid dimer peak at 1720 and at 1690 cm−1, respectively (Fig. 6). In addition, the peak at 1585 cm−1 was attributed to the benzoyl carbonyl group attached to a nitrogen atom. The absorbance of the drug dimer peaks disappeared after the granulation process was optimised in all formulations, and only one slightly shifted peak at 1680 cm−1 was visible. This could be attributed to the intermolecular interactions associated with crystalline BMA. Interestingly, the increase in the concentration of the drug in formulations showed an increase in the intensity of the characteristic peak at 1680 cm−1 which could be due to the presence of more NH– in the formulation as it only is present in the BMA. Previous study revealed that owing to the close proximity of the pKa values of SiO2 to that of BMA, the silanol group from US2 can become amphoteric, functioning as a Bronsted acid or as a Bronsted base [12, 27]. Therefore, due to the local electronegativities of –COOH and –Si-OH from the drug and US2, respectively –C-O-Si is formed as a result of ionic bonding. These foregoing claims have been outlined in the molecular modelling predictions as depicted in Fig. 6. As can be seen in the image, depending on the initial positioning of the BMA molecule, multiple bonding patterns were identified. However, after energy optimisation, the highest proximity has been observed for the interaction between the silanol group of the carrier and the carboxyl group of the drug (~ 4.07 Å). It has also been outlined that both the carbonyl group and amine group within the drug molecule could form bonds (e.g. non-covalent H bonds) with the –Si-OH group in the BMA, as indicated by the optimal distances between the bond donor and acceptor ~ 15.08 and ~ 11.50 Å, respectively.
Also, the benzoyl carbonyl peak at 1585 cm−1 becomes broader as a function of decreasing drug concentrations, indicating increasing amorphicity of BMA. It can be claimed that the higher the BMA amount, the sharper the benzoyl carbonyl peak thus stronger the interactions. The high intense stretch at 1680 cm−1 in US2 1 where the drug content is the highest (50% w/w) indicates that intermolecular interactions are favoured with the increase in the BMA concentration. In contrast, as expected, the characteristic dimer peaks of BMA are present at the same position for all PM formulations (data not shown).
The DVS data presented in Fig. 7a, b showed that the US2 2.5 BMA (~ 30% w/w) formulation sample desorbed ca. 4% w/w moisture at 0% RH suggesting that the sample already contained this moisture. This is confirmed by the water uptake phenomenon, ca. 4% w/w up to 50% RH, which implies that at ambient condition, this sample is hygroscopic. The hygroscopic nature is also confirmed by the hygroscopicity classification as per the Ph. Eur. in Table 1 . So, a care must be taken to formulate and store this sample after production during future developmental work. A further water uptake up to 6% w/w at 80% RH, followed by a sharp increase in weight gain up to ca. 10% w/w, which even did not reach equilibrium, demonstrates that this sample has an affinity to absorb large quantity of moisture upon exposure to high humidity. Interestingly, no weight loss was observed to suggest crystallisation of an amorphous material, due to water acting as a plasticiser, indicating that water is not a good plasticiser for this material. Importantly, this implies that this formulation could be a stable one over a long period of time at high humidity if water absorption is controlled. The sample did not hold onto any gained mass during desorption cycle suggesting that the sample is possibly non-porous in nature and post-DVS sample also did not show any obvious physical appearance change. Similar results were obtained for other formulations. The effect of the moisture on the solid state of the extruded granules showed that the manufactured formulations are stable even at higher drug concentration (up to 50% w/w).
Solution calorimetry (SolCal)
The solution calorimetry data presented in Table 2 suggested a reproducible data set for a biphasic system. It clearly demonstrates and distinguishes heat of solution of different materials. There are two interesting aspects of these data set: the first one being all formulation samples with different % w/w of the API loading showed a response which is different to physical mix (theoretically expected), and had there been a physical mix made for those formulation samples as their theoretical response were different than the experimental response sugggesting that the formulations were indeed not a mere physical mix. This hypothesis is effectively validated by the data obtained for 50:50 (w/w) physical mix (PM) between BMA and US2. The second aspect is that the US2 1 with 50% w/w drug did not follow the expected trend as the other US2 4 and US2 2.5 samples suggesting that the API load was optimised up to ~ 30% w/w or in between 30 and 40% w/w.
Generally, amorphous samples exhibit exothermic response; it is possible that the US2 2.5 sample is higher in amorphous nature than its US2 4 and US2 1 counterparts. However, the reason could be different in both cases. Based on these data, the relationship between 20% w/w (US2 4) and 30% w/w (US2 2.5) loaded samples is that US2 2.5 sample is higher in amorphous than the US2 4 and, therefore, will be stable for longer as a solid dispersion product. This foregoing claim complements the finding from the release data of BMA achieved at 30 min. As can be seen in Fig. 8, the release of the drug was increased up to the 30% w/w drug loading (US2 2.5). With the increase in the content of the drug, the release seemed to have decreased possibly due to the drug collapsing into its crystalline form. However, anything above 40% w/w drug loaded samples showed that the optimum level of drug loading has been achieved and the sample will no longer exhibit higher amorphous nature or exothermic response as compared to 30% w/w loaded sample. These data suggest that the solution calorimetry could be effectively used to distinguish different solid dispersion products with varying drug loadings and be interrelated with the most optimised formulation as a function of the increased release of the drug. As the name suggests, it is a precision solution calorimetry technique; therefore, room temperature, method development, sample preparation, solvent selection, etc. require years of experience to reproduce consistent data especially in complex systems like solid dispersion, granulated formulations using this technique.