Molecular solid dispersions are advantageous, since they yield improved bioavailabilities [1, 2], which is a common problem in the delivery of poorly soluble drugs (e.g. [3, 4]). The reason for improved bioavailabilities is twofold: First, in a molecular dispersion the drug size is maximally reduced. Second, molecular dispersions frequently contain the drug in its amorphous state, which shows increased apparent solubility compared to its crystalline counterpart. Moreover, advanced formulations (i.e., co-crystals and in situ salts) or structured products (i.e., by co-extrusion) can be obtained.
HME does not readily deliver a final formulation product that can be administered to the patient. Instead, HME provides molten material that needs to be further processed via a downstream process. Thereby, a variety of different dosage forms, including intermediate products that need further processing (e.g., granules), are manufactured. This clearly shows that, after HME, a variety of additional processing steps are required, which may affect the final dosage form performance and stability.
Similar to HME, injection molding (IM) is a melt processing technique. It offers the opportunity to directly process molten material into a final product of any desired shape, while maintaining the advantages of a solid dispersion. IM is a semi-continuous process and comprises five processing steps (Figure 1). During IM thermoplastic materials are typically melted using a single-screw extruder (Figure 1, Step 1). The molten material is accumulated in the antechamber in front of the screw and plasticization is completed when a predefined volume is reached (Figure 1, Step 2). Subsequently, the molten material is injected into a closed, shape-specific mold cavity (Figure 1, Step 3), where it cools down and solidifies. During the packing and cooling step, the injection pressure is maintained to supply the mold with fresh material. Thereby, volume shrinkage during cooling is compensated. Finally, the product (e.g. tablet) is ejected from the mold (Figure 1, Step 5).
In certain cases IM can be applied to directly process the primary powders (i.e., drug and excipients) into a final dosage form. However, most frequently, IM is applied to process homogeneous material manufactured via HME, since conventional IM uses single-screw plasticizing units with limited mixing capabilities. Thereby, application of the primary powders as feeding material would yield an inhomogeneous product with poor in-vivo performance.
The present study addresses production of tablets via IM that contain a poorly soluble model drug as an amorphous solid dispersion. Therefore, we applied a simple two-component system comprising fenofibrate as the model drug and polyvinyl caprolactame-polyvinyl acetate-polyethylene glycol graft copolymer (Soluplus®, BASF) as the matrix former. Due to its poor water solubility, fenofibrate dissolution is expected to limit fenofibrate absorption. Consequently, proper formulation strategies need to be applied to ensure efficient and safe patient treatment.
Pellets containing 10% fenofibrate and 90% graft copolymer were prepared via HME. Subsequently, the pellets were processed into tablets in a single step using an Engel e-mac 50/50 IM machine (Figure 2A) equipped with an 18 mm single-screw plasticizing unit. The mold was constructed with a cold runner system and six cavities (Figure 2B). Individual tablets were obtained by manually removing the sprue. The shape of the mold served to produce cylindrical tablets with a diameter of 13 mm and a height of 5 mm.
The tablets were characterized via differential scanning calorimetry (DSC) with respect to the solid state of both fenofibrate and the graft copolymer. Moreover, the effect of the solid state on the in-vitro dissolution performance was evaluated.
Results and Discussion
Tablets prepared via IM were yellowish with a smooth surface (Figure 3). They were glassy in their appearance and their weight was 620 mg, corresponding to a single dose of 62 mg fenofibrate for 10% drug loading. The cycle time during IM was approximately 1 min, which allows production of 360 tablets per hour. The yield (i.e., ratio of tablet weight to total weight) was rather low, i.e., around 40% with the used setup. This can be improved by applying a hot runner system and/or a higher number of cavities in the mold, which will be the focus of future work.
The solid state of fenofibrate of the pellets prepared via HME and of the tablets prepared via IM was investigated using DSC. For comparison reasons, the primary powders and the physical blend resembling the formulation were investigated as well. The results are summarized in Figure 4: The thermogram of the physical blend shows an endothermic peak around 80°C correlating to the melting of fenofibrate. As the glass transitions of Soluplus occurs at the same temperature of 80°C, it was not clearly detectable in the thermogram of the physical blend. Once the powder blend was subjected to a thermal process that was HME and IM, the thermograms did not include the melting peak of fenofibrate, indicating the absence (or only very low amounts) of crystalline drug. This suggests formation of a solid dispersion containing both, fenofibrate and the graft copolymer in their amorphous states during HME and IM. Consequently, the dissolution rates of fenofibrate pellets prepared via HME and tablets manufactured via IM were markedly increased compared to the powder blend (Figure 5). Obviously, fenofibrate dissolution was not improved by simply blending the drug with the polymer, but by thermal treatment of the blend. Fenofibrate release from the pellets was rapid and was completed within 30 minutes. The tablets release profiles showed a zero-order release mechanism over two hours in hydrochloric acid, where, finally, 60% of the drug was found in the dissolution medium. Clearly, the dissolution profiles of pellets and tablets were different, although the DSC measurements indicated that both, pellets and tablets contained fenofibrate in its amorphous state. The differences are not attributed to the solid-state characteristics, but to decreased surface-to-volume ratios of tablets compared to pellets. Hence, according to the Noyes-Whitney equation, the dissolution rate is slowed for identical drug loadings and diffusion coefficients.
Conclusion and Outlook
Overall, the IM process applied was suitable for tablet production, which yield improved dissolution characteristics of fenofibrate due to the formation of a solid dispersion.
The focus of our work is to gain a fundamental understanding of processing, release and stability behavior of IM tablets, based on detailed material and process characterization, such as viscosity and melt behavior, miscibility, thermal behavior, just to mention some examples. Deep process understanding reduces development effort during transfer from screening methods to pilot scale production. Furthermore, it allows tailoring product properties to a significant extent. Thus, it is a necessary prerequisite for a successful implementation of injection molding as manufacturing technology in the pharmaceutical industry.
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2. Ford, J.L., The current status of solid dispersions. Phar. Acta Helv., 1986. 61: p. 69-88.
3. Forster, A., et al., Selection of excipients for melt extrusion with two poorly water-soluble drugs by solubility parameter calculation and thermal analysis. International Journal of Pharmaceutics, 2001. 226(1–2): p. 147-161 http://dx.doi.org/10.1016/S0378-5173(01)00801-8.
4. Chokshi, R.J., et al., Characterization of physico-mechanical properties of indomethacin and polymers to assess their suitability for hot-melt extrusion processs as a means to manufacture solid dispersion/solution. Journal of Pharmaceutical Sciences, 2005. 94(11): p. 2463-2474 http://dx.doi.org/10.1002/jps.20385.
The “Pharmaceutical Engineering and Particle Technology” area at the Institute of Process and Particle Engineering has developed from a group of researchers around Prof. Johannes Khinast in Fall 2005. Initially focused on catalysis and direct numerical simulations of bubbly flows, Prof. Khinast’s group has formed three sub-groups dedicated to research in the fields of applied chemistry and continuous processing, manufacturing processes for the pharmaceutical industry, and simulation science. In a highly interdisciplinary environment, our area is eager to gain a more fundamental understanding of
- transport process in (bio)reactors,
- production of heterogeneous catalysts and (nano)particles,
- (chromatographic) separation processes,
- pharmaceutical polymer processing,
- multiphase and granular flows, as well as
- transport processes in complex fluids.
A main focus, with respect to teaching, is student training in the area of pharmaceutical engineering, transport phenomena and particle technology. Our research complements that of our sister organization “Research Center Pharmaceutical Engineering GmbH”, and is tightly connected to leading national and international research institutions. This makes our area an attractive partner for the industry, and brings us into a position for applying and winning Austria- and Europe-wide research grants.
Please find further information at: http://ippt.tugraz.at