Results of field testing in a R&D case study
The question whether low-dose pharmaceutical formulations with micronized APIs are suitable for a DC process was challenged
using a water-sensitive R&D API at only 0.4% in the final dosage form (0.5 mg API in a 120-mg tablet). Wet granulation could
not be applied because of the water-sensitivity of the API. The micronized API (Dv50 10 μm), therefore, was premixed for 30
min using a shaker-mixer (Turbula T2C) with 15% of the total amount of DC-grade mannitol DC-Mannitol M (Dv50 200 μm) and mixed
with the rest of the formulation using a Turbula T20P (Bachofen AG) (see Figure 8). A test run of 2 h on a rotary press (Korsch Pharmapress PH230, Korsch AG) was performed at two different rotation speeds
(40,000 and 80,000 tablets/h). The tablets were assessed for their weight, hardness, and disintegration time.
Figure 8: Composition of the investigated pharmaceutical formulation used for the R&D case study.
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 (see Table II). Content uniformity was measured to be ± 1.8 %.
Table II: Comparison of tablets manufactured at different speeds of the rotary press.
Although the concept of ordered mixtures has been extensively studied and reported, little was known about the mechanisms
and reasons behind ordered mixtures (6–9). The results clearly show that the effect of ordered mixtures can be found with
DC-mannitols as a function of surface area and structure. To a greater extent, this functionality can be found for spray-dried
qualities with a porous surface structure. A large surface area is helpful for good binding capacity. Stable mixtures are
not only achieved with components of similar particle sizes as the literature suggests. It is also possible to achieve a stable
mixture of micronized API particles (< 15 μm) with a DC-mannitol with a mean particle size of 200 μm. The stability is caused
by an adsorptive binding force strong enough to withstand the mechanical separation forces. This effect was successfully demonstrated
for hydrophilic and hydrophobic APIs. This result confirms the feasibility of DC for low-dose applications with acceptable
content uniformity as the example showed. It also helps to show that micronized APIs at higher concentrations can be applied
in solid formulations to enhance their solubility. This approach can be applied for DC, sachet formulations, or in roller
H. Leonhard Ohrem* is a technical manager, email@example.com
Roberto Ognibene is head of the formulation laboratory, and Thorsten Wedel is a pharmaceutical engineer, all with Merck KGaA, Darmstadt, Germany 64271.
*To whom all correspondence should be addressed.
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