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
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.