Milled drug suspensions were refrigerated at 8 °C for a period of 7 days to examine the aging effects. Note that all suspensions had 2.5% HPC as baseline stabilizer. All milled suspensions had smaller particles in the presence of SDS in addition to HPC (Table 2.2), which indicates that SDS helped to suppress the particle aggregation for
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all drugs during the milling. After storage, the characteristic sizes of GF and PB suspensions with SDS remained unchanged within experimental accuracy, and AZD exhibited a slight increase in d90. On the other hand, FNB and IBU suspensions with SDS exhibited significant size increase, whereas the suspensions of the same drugs without SDS (having HPC as the sole stabilizer) did not exhibit such a high size increase during the storage. While SDS helped to suppress aggregation of FNB and IBU particles during wet media milling, it unfortunately caused the growth of particles over 7 days, thus pointing to a need to optimize the SDS concentration.
The increase in particle size during storage can be attributed to two mechanisms: Brownian aggregation of the particles caused by insufficient stabilization and/or particle growth due to Ostwald ripening (Knieke et al., 2013;
Verma et al., 2011). 2.5% HPC alone was not sufficient to stabilize FNB and GF suspensions via steric stabilization alone; hence, FNB and GF suspensions were already aggregated during the milling and interestingly GF showed no increase and FNB showed about 15% increase in the median size after 7-day storage (Table 2.2).
The median size increase was less than 15% for all drugs in the absence of SDS. In the presence of 0.5% SDS, FNB and IBU showed a significant increase in both d50 and d90 after 7-day storage. The SEM image of FNB suspension after 7-day storage shows approximately 12 µm rhombohedral primary particles (Figure 2.3(f)) that did not exist in the milled suspension (Figure 2.3(e)). The presence of such rhombohedral crystals implies that the observed size increase was governed more by the Ostwald ripening than the aggregation. The water-solubility of FNB increases significantly with an increase in surfactant concentration especially above the critical micelle
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concentration (CMC) of SDS, which in turn facilitates the ripening process (Ng et al., 1996). A similar effect with SDS was observed by Gosh et al. (2011) and Verma et al.
(2011) for several drugs.
To mitigate Ostwald ripening and possible size increase during storage, while maintaining the positive effects imparted by combined HPC–SDS during the milling, the SDS concentration should be optimized. Knieke et al. (2013) constructed dynamic equilibrium curves to optimize surfactant concentration at constant HPMC loading with several SDS concentrations in a single milling experiment, and the particle sizes obtained after milling and after 7-day storage were compared to find the optimal SDS loading. In the current study, such a method was not used; but, an attempt was made to prove that optimization of the SDS concentration can mitigate the Ostwald ripening significantly. When 0.05% of SDS (below CMC), instead of 0.5% SDS (above CMC), was used in the presence of 2.5% HPC, FNB particles with d50 and d90 of 0.157 µm and 0.248 µm, respectively, were obtained after 120 min milling, and the d50 and d90 values were 0.171 µm and 0.342 µm, respectively, after 7-day storage. At 0.05% SDS, the positive impact of SDS on the suppression of particle aggregation was still maintained, while the negative impact via Ostwald ripening was significantly reduced, but not eliminated completely. Moreover, the FNB suspensions with HPC and 0.05% SDS had smaller sizes than those with HPC alone both after milling and after storage, again confirming the success of the HPC–SDS combination strategy. A similar reduction in SDS concentration could be applied to IBU case; however, this was not explored here because the beneficial effect of even 0.5% SDS was not pronounced for the milled IBU suspension as compared with the milled FNB
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suspension, which can be inferred from the relatively small difference between particle sizes right after milling in the absence/presence of SDS (see Table 2.2).
Additionally, the size increase during storage was much less pronounced for IBU than for FNB; hence, the benefit of using a smaller SDS concentration would be negligibly small. In a future study, the relative extent of Ostwald ripening could be investigated for different storage times and conditions, and SDS concentration could be optimized using the approach proposed by Knieke et al. (2013).
Since the milled suspensions are intended for immediate drying for eventual solid dosage manufacture, long-term stability of the suspensions was not a major focus of this work; it was studied only for one of the drugs, i.e., GF, which exhibited pronounced difference in the aggregation state depending on the presence/absence of SDS. When HPC was the sole stabilizer, not only did the GF particles aggregated extensively (refer to Table 2.2), but also they phase-segregated or settled after long-term storage due to the presence of coarse micron-sized aggregates (Figure 2.5(a) and (b)). The GF suspension with 2.5% HPC–0.5% SDS exhibited good long-term stability even without necessitating further formulation optimization. It did not show phase-segregation even after 6 months because all particles were colloidal and 90% of particles were smaller than ~300 nm (Figure 2.5(c) and (d)).
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Figure 2.5 Images showing GF suspensions (a) after 120 milling in the presence of HPC alone (d50 = 1.343 µm and d90 = 2.183 µm), (b) after 6-month storage in the presence of HPC alone (d50 = 1.949 µm and d90 = 2.374 µm), (c) after 120 milling in the presence of HPC–SDS (d50 = 0.160 µm and d90 = 0.208 µm), (d) after 6-month storage in the presence of HPC–SDS (d50 = 0.186 µm and d90 = 0.301 µm).