Solid Formulations

Nano Suspensions, Particle Engineering and Composite Particles

For solid formulations, nano suspensions have been used to develop fast-dissolve dosage forms and engineered composite particles that are compressable into conventional (bioavailability enhanced) tablets, e.g. fenofibrate.

The drug delivery challenge for poorly water-soluble compounds can be addressed via multiple formulation approaches with differing underlying mechanisms of solubility modification. The most ‘tried and tested’ method is particle size reduction, often to the low micron-size range. Micronization increases the drug’s surface area per weight and increases the dissolution rate of poorly soluble particles. Micronization may be ineffective for compounds with extreme solubility issues.

In recent years, particle size reduction approaches have advanced into the sub-micron particle size region, i.e. 1-1000 nanometer range, which produces huge increases in the surface area of drug. As a result, the dissolution rate payoff may be quite large. Added benefits of oral nanoparticle delivery for poorly water-soluble drugs includes elimination of food-effects while maintaining the drug substance in its original and most chemically stable solid form.

Nanoparticles may be delivered orally as a liquid nanosuspension or as a solid dosage form. Stabilization of nanoparticles in the solid state is typically achieved by spray drying or freeze-drying, with the technical requirement being a unit dose that can readily re-suspend the nanoparticles to the starting particle size. Nanoparticles remain the subject of extensive, ongoing drug delivery research.

Hot Melt Extrudates

Twin-screw melt-extrusion, with controlled pressure, heat and shear stress, is a powerful way to de-aggregate API molecules and distributing them homogeneously within the delivery matrix.6 Since the carrier is usually amorphous, the active ingredient is incorporated either in a crystalline state, an amorphous state, or through a molecular solution. For the latter the most reliable and stable formulations involve drug that is molecularly dissolved below its saturation solubility within a particular matrix. Dissolution of this formulation in gastric or intestinal fluids results in a supersaturated solution of drug with enhanced dissolution and bioavailability.

Hot melt extrusion provides numerous benefits, including improved bioavailability for poorly-soluble, low-permeability molecules. With a wide choice of dispersion techniques and matrices, hot melt provides a relatively rapid development path to controlled- or sustained-release formulations. The technique is moreover a continuous, efficient process resulting in little waste of API or matrix.

Spray Dried Dispersion

Solid dispersions through spray drying are formed by dissolving the active ingredient, a dispersant (generally a polymer), and any other desired excipients in an organic solvent.7 The solution is then sprayed (atomized) into a heated chamber where the organic solvent evaporates, leaving an amorphous powder suitable for further processing if desired. The higher energy state of the amorphous powder results in more rapid and complete dissolution. Formulation scientists may alter relevant powder density, particle size, and morphology, or manipulate solvent type, ingredient concentration, spray rate, inlet/outlet temperature, and other parameters to achieve the desired dissolution profile. Spray dried dispersion is a rapid, cost-effective, and scalable method of manufacturing amorphous particles to overcome low solubility issues associated with low bioavailability.

6Crowley, M.M. , Zhang, F. Repka, M.A. Thumma, S. Upadhye, S.B. Battu, S.K. McGinity, J.W. and Martin, C. (2007) Pharmaceutical Applications of Hot-Melt Extrusion: Part I 33(9): 909-926.

7Friesen, D.T. Shanker, R. Crew, M. Smithey, D.T. Curatolo, W.J. Nightingale, J.A.S. (2008) Hydroxypropyl Methylcellulose Acetate Succinate-Based Spray-Dried Dispersions: An Overview Mol. Pharmaceutics 5(6): 1003–1019.

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