There are several reasons to micronize APIs in a solid-dosage formulation. Many new drug molecules are poorly soluble, and
one means to enhance solubility is to enlarge surface area by micronizing the API. Obtaining a homogenous mixture of the micronized
API and excipients in a solid dose and maintaining product stability, however, can be challenging. Additionally, micronized
APIs are used in the formulation of highly potent drugs that require low dosage. In this case, content uniformity is crucial
and difficult to achieve when seeking to evenly distribute content of less than 1% API in a solid formulation.
The pure physical mixture based on statistical distribution often has no stability of homogeneity. For this reason, many formulators
switch to more expensive wet- or dry-granulation processes instead of direct compression (DC) or sachet formulations. A mixture
has the best chance for stability if the particles of the API and excipients are of the same size range (1). For handling
reasons, the mixture of excipients and API should be in a granulate form rather than in powdered form.
The purpose of this study was to evaluate whether such APIs could create stable mixtures with larger excipient particles and
support a DC-tableting process with good content uniformity. An earlier study demonstrated the stability of so-called "ordered
mixtures" with spray-dried sorbitol and much smaller API particles (2, 3). Hersey first introduced the concept of ordered
mixtures to explain the behavior of interacting particles in a powder mixture (4).
These examples from the literature dealt with spray-dried sorbitol, which at the time, was a rare example of a DC excipient.
Today, mannitol is used as a DC excipient due to its inertness, its low hygroscopicity and its fast-release qualities. The
study in this article focuses on different DC-grades of mannitol available on the market.
Materials and methods
Table I: Physical characteristics of applied excipients and APIs*.
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Two types of spray-dried DC-mannitol were used, respectively named in this study as DC-Mannitol A and DC-Mannitol M, and one
type of granulated mannitol, DC-Mannitol B (see Table I). The model APIs used were ascorbic acid as an example of a hydrophilic compound and riboflavin as a hydrophobic compound.
Both APIs were micronized on a pin mill before using them for this case study (see Table I).
API–mannitol mixtures (batch size 300 g) were prepared using a shaker-mixer (Turbula T2C, Willy A. Bachofen AG Maschinenfabrik).
To evaluate the quality of mixing, the homogeneity was measured by taking six samples from the mixtures and applying a sample
divider (Retsch Type RT 6.5, Retsch AG) after a specified period of mixing time (2, 5, 10, 20 and 30 min). The procedure was
repeated three times.
Figure 1: The relative standard deviation (RSD) of the API content in relation to the mixing time of the API–direct compresson
(DC)-Mannitol M samples (drug load 1% w/w). (FIGURES ARE COURTESY OF THE AUTHOR)
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The API content in each sample was analyzed (n = 18). For ascorbic acid, the content was determined through a volumetric analysis
by titration with an iodine solution (TitriPUR, Merck KGaA), which provided an accuracy of measurement with a relative standard
deviation (RSD) of 0.12%. The riboflavin content was determined spectrophotometrically at 444 nm according to the European Pharmacopoeia (5). The RSD of the API concentration was examined as a function of mixing time (see Figures 1 and 2).
Figure 2: Relative standard deviation (RSD) of the API concentration (1% ascorbic acid/riboflavin, micronized) in samples
containing a model API and different direct-compression (DC)-mannitols as excipients.
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To challenge the mixture stability and to show the strength of adsorption of low-dose formulations, API–DC-mannitol mixtures
with a drug content of 1% and 3% were applied to an Alpine air jet-sieve (A 200 LS, Hosokawa Alpine) and analyzed for their
drug content after 15 min of airflow. The applied mesh size was 40 μm, and the vacuum pressure was 2000 mPa. Separately, the
capability of a stable, direct-compression process was further investigated using a water-sensitive low-dose drug in a pharmaceutical
formulation. The results of this investigation are later discussed under the "Results of field testing in a R&D case study"
portion of this article.
