The percentage of sulfate Salb deliver 12µg drug per dose.
or even more per dose. Consequently, it i percentage on the formulation performance. one of which contained 0.72% fine sul additives, and the other contained lactose to keep the percentage
sulfate Salbutamol would deliver about 120 shown in Table 7.25, indicating uniform blends.
Table 7.25: The blend drug content uniformity of formulation
API percentage(n=6)
AVG％
RSD％
The TI performance result is
results, the percentage of API does
The microscope images of different-source lactose a, SV003; b, LH200 (milled)
he influence of API on formulation performance
Salbutamol in the blend is set at 0.72% for most experiments per dose. Nevertheless, many commercial products deliver
onsequently, it is necessary to study the influence
percentage on the formulation performance. Two powder formulations were prepared, 0.72% fine sulfate Salbutamol and about 20% fine lactose as
contained 7.2% fine sulfate Salbutamol and about 13
lactose to keep the percentage of fine particles constant. The formulation containing 7.2% would deliver about 120µg drug per dose. The content uniformity is shown in Table 7.25, indicating uniform blends.
blend drug content uniformity of formulations with different percentage API.
API=0.72% API=7.2%
0.62 5.74
2.9% 4.4%
is shown in Fig.7.20 and Table 7.26. As we can
lts, the percentage of API does not affect the FPP values but the blister remains lactose.
t at 0.72% for most experiments to products deliver 100µg API ssary to study the influence of the API wder formulations were prepared, and about 20% fine lactose as and about 13% fine of fine particles constant. The formulation containing 7.2% The content uniformity is
with different-
API=7.2% 5.74 4.4%
As we can see from the values but the blister remains
slightly. The high percentage
blister remains, because more API particles mean more More fine drug particles do
fine particle from carriers. T since it greatly expands device
only the fumarate formoterol inhalers. higher than low-API formulation
constant during storage and transportation.
Figure 7.20: The FPF and blister remains of formula
Table 7.26: The FPF and blist TI test (n=2)
percentage of the API in formulation results in a larger
more API particles mean more adherences to the blister wall. not affect a disaggregation of agglomerates or
This result is especially meaningful for the Inhaler device application to match different marketed products but only the fumarate formoterol inhalers. Although the fraction of blister remains
API formulation, it is still acceptable as long as the value remain constant during storage and transportation.
The FPF and blister remains of formulation with different-percentage API.
The FPF and blister remains results of the different - percentage API TI test (n=2) Percentage of API
0.72% 7.20% FPF-AVG 48.6% 49.0% SD 0.1% 0.8% Remains- AVG 29.5% 36.8% SD 4.5% 0.8% a larger fraction of to the blister wall. ation of agglomerates or detachment of especially meaningful for the Inhaler-WU2011, tch different marketed products but not blister remains is a little s still acceptable as long as the value remain
tion with
The influence of API size on formulation performance is studied. The sulfate Salbutamol particle is micronized by a jet-mill to produce API with different size distribution. The size distribution results are shown in Table 7.2. Then formulations containing 0.72% of these API, about 5% fine lactose and 94% Inhalac 230 were prepared. The drug content uniformity result shown in Table 7.27 demonstrates an excellent uniformity.
Table 7.27: The blend drug content uniformity of formulation with different-size API
API size (µm)
API percentage(n=6) X50=1.33 X50=1.57 X50=2.24
AVG％ 0.61 0.60 0.59
RSD％ 1.5% 0.8% 0.8%
As shown in Fig.7.21 and Table 7.28, the FPF and blister remains are not sensitive to the API particle size. This result not only provides an investigation into the influence of API size on the formulation performance, but also demonstrates that even if the size of API fluctuates within a certain range, the performance does not change obviously. This conclusion is greatly useful for large-scale production. Usually, some critical parameters of commercial production should be set in a range rather than a specific value. A lot of work should be carried out to validate the acceptable range for the critical parameters. This is a core viewpoint in the Common Technical Document (CTD) by the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH).
There is some literature focusing on the influence of the API particle size on the inhaler performance. Yet, most of the API particles are prepared by spray-drying; hence they can not provide plenty of useful information for jet-milled particles. For instance, Chew reported that the spray-dried disodium cromoglycate with 2.3µm of MMD exhibited lower FPF then particles with 3.7 or 5.2µm of MMD[155]. When considering the jet-milled API particles, it was reported that the larger size would decrease the FPF and performance stability in pMDI[156].
Figure 7.21: The FPF and blister remains of formula Table 7.28: The FPF and blister remain
TI test (n=2) FPF-AVG
SD Remains-AVG
SD
The mixing sequence of API i performance improvement by
coarse lactose first, and then the API i
based on an assumption that the fine lactose would carriers and assist the detach
API and fine lactose first and then fine mixed. The percentage of the API
230 for both methods. As shown in Table blend drug content uniformity and both
The FPF and blister remains of formulation with different The FPF and blister remains results of different-size API
API size (µm) X50=2.24 X50=1.57 19.6% 19.0% 0.6% 1.2% 20.1% 19.1% 2.8% 4.5%
he mixing sequence of API is further investigated to study the
performance improvement by fine lactose. One method is to mix the fine lactose with , and then the API is added into the lactose system. This procedure
tion that the fine lactose would occupy the active site on the large carriers and assist the detachment of API from carriers. Another method i
and then fine particle system is added into coarse lactose and the API is 0.72%, with 5% fine lactose and about 94% Inhalac s shown in Table 7.29, the mixing sequence does
blend drug content uniformity and both mixtures show good uniformity.
tion with different-size API. size API X50=1.33 17.3% 1.4% 22.1% 0.8%
s further investigated to study the mechanism of s to mix the fine lactose with This procedure is occupy the active site on the large method is to blend the added into coarse lactose and with 5% fine lactose and about 94% Inhalac does not affect the
Table 7.29: The blend drug content uniformity of different mixing sequence API
percentage(n=6)
AVG％
RSD％
According to Fig.7.22 and Table
a little higher FPF and less blister remains than the other one. contradictory to the common
that the API-fines agglomerates are
those agglomerates can be dispersed easily during delivery. agglomerates formation, the adhesion of API to blister
Figure 7.22: The FPF and blister
blend drug content uniformity of different mixing sequence API mixing sequence
(API+fines) +coarse API+(fines+coarse)
0.58 0.59
1.9% 1.1%
and Table 7.30, the (API+Fines) +Coarse mixing sequence er FPF and less blister remains than the other one. This observation contradictory to the common “active site” or “high-energy site” hypothesis. It i
fines agglomerates are formed in the (API+Fines) +Coarse method. And be dispersed easily during delivery. As a result of API the adhesion of API to blister wall decreased.
The FPF and blister remain of formulation with different mixing sequence for the API.
blend drug content uniformity of different mixing sequence for API
API+(fines+coarse) 0.59 1.1%
mixing sequence exhibit This observation is hypothesis. It is inferred +Coarse method. And s a result of API-Fines
Table 7.30: The FPF and blister remains results of different API mixing sequences
API mixing sequence
TI test (n=2) (API+fines)+coarse API+(fines+coarse)
FPF-AVG 27.2% 21.6%
SD 4.6% 1.0%
Remains-
AVG 14.3% 21.0%
SD 1.0% 2.3%