New Technologies - APV

Micronised APIs in direct compression
and ascorbic acid. Here, fewer areas suitable for the absorption of the API
are present. The overall surface is less structured. A similar distribution on
the carrier surface was determined for the hydrophobic model drug riboflavin
(Fig. 6).
Figure 6: Mixture of Parteck® M 200 with micronized riboflavin
(drug load 1% w/w). Light microscope with 40x magnification.
The yellow particles of API are clearly visible in the porosity of
the carrier surface.
The importance of the surface area and the pore volume of the additive for
the homogeneity of the mixture was demonstrated. Next, the surface area
and porosity of various additives for direct compression were analyzed
using the BET method (nitrogen adsorption). Since the API is adsorbed to a
porous surface, the observed differences between the excipients may give
rise to different behavior in the adsorption of micronised APIs (Fig. 7).
This study has shown that stable mixtures of much smaller micronized API
particles with DC-excipients can be achieved. Is this suitable for a direct
compression process in a real formulation?
Figure 7: Comparison of the surface area and pore volumes of
different excipients for direct compression.
13 11
New Technologies
R&D Case Study: Results from a Field
Testing
The question of whether low-dose pharmaceutical formulations with micronized
API can be prepared by a DC process was tested using a watersensitive
R&D-API at only 0.4% in the final dosage form (0.5 mg API in 120
mg tablet). Wet granulation could not be applied, because of the watersensitivity
of the API. So the micronized API (Dv50 10 µm) was premixed for
30 minusing a Turbula® T2C shaker-mixer with 15% of the total amount of
DC-grade mannitol Parteck® M (Dv50 200 µm), then mixed with the rest of
the formulation (Fig. 8). A test run of 2 h on a Korsch Pharmapress PH230
rotary press (Korsch AG, Berlin, Germany) was performed at two different
rotation speeds (40’000 and 80’000 T/h). The tablets were assessed for
their weight, hardness and disintegration time.
This result was surprisingly good, as constant values were detected for
tablet weight (RSD 0.6 – 0.9%), tablet hardness (RSD 4.1%) and disintegration
time (Table 2). Content uniformity was measured to be ± 1.8 %.
Figure 8: Composition of the pharmaceutical formulation used
for the R&D case study.
Table 2: Comparison of tablets manufactured at different speeds of the
rotary press.
Tablet weight
Conclusion
40‘000 Tablets/h 80‘000 Tablets/h
120.1 mg (RSD
0.6%)
118.8 mg (RSD 0.9%)
Tablet hardness 178 N (RSD 4.1%) 173 N (RSD 4.1%)
Disintegration time 3'25'' 3'22''
Although the concept of ordered mixtures has been extensively studied and
reported [6,7,8,9], little was known about the underlying mechanisms and
rationale. The results show clearly that the effect of ordered mixtures can
be seen with DC-mannitols as a function of surface area and structure. The
effect is greatest with for spray-dried qualities with a porous surface structure.
A large surface area is necessary for a good binding capacity. Stable