(550c) Improving Dissolution Kinetics of Pharmaceuticals By Fluidized Bed Impregnation

Authors: 
Grigorov, P. I., Rutgers University
Glasser, B. J., Rutgers University
Muzzio, F. J., Rutgers University

According to the current Biopharmaceutics Classification System (BCS) adopted by the U.S. Federal Drug Administration (FDA), drug substances are categorized into four main classes, based on their solubility and permeability. Two of those classes (BCS classes II and IV) are characterized with low solubility. The trend in the past decade has been toward steady increase in the number of active pharmaceutical ingredients (APIs) belonging to BCS classes II and IV. It has been estimated that up to 60% of new chemical entities fall in the low solubility class, compared to 39% for marked drugs. This trend towards decrease in API solubility is undoubtedly one of the main hurdles for formulators today, as they continuously strive to develop novel formulations capable of effectively delivering the drug into the blood stream.

API solubility has a direct effect on the drug’s bioavailability and therefore its efficacy. The absorption of BCS Class II and IV compounds and the resulting blood concentration-time profile depends on the rate-limiting step, which can be one of the following: permeability limited, dissolution limited and solubility limited. For poorly-soluble compounds, improving the rate (for dissolution limited) and the extent of dissolution (for solubility limited) will directly increase their bioavailability. There are two main techniques that are widely used today for improving dissolution rate and increasing solubility. The first technique involves particle size reduction as suggested by the Nernst-Brunner/Noyes-Whitney equation, where the dissolution rate for any API is proportional to the surface area available for dissolution. Solubility of any substance is a thermodynamic property, which among other environmental factors (solvent nature, pH and temperature) depends strongly on the chemical or physical structure of the substance itself (e.g. salts, crystalline or amorphous solids, solvates, co-crystals). Many variations of these two main techniques for improving dissolution rate and increasing solubility are employed into today’s development or marketed drug formulations. The most common  include various bottom up or top down approaches for size reduction and numerous means for producing amorphous materials (e.g. spray drying, freeze drying, hot-melt extrusion, polymer additives). Often these methods have major challenges and limitations associated with: difficulty in control or scale up, API stability, applicability to wide range of APIs, high cost, etc.

In this work we present a drug formulation method that is capable of increasing significantly the dissolution kinetics of a poorly soluble API (Fenofibrate), which shows a high degree of simplicity compared to many of the traditional methods. The method involves impregnation of the API into highly porous excipient in a fluidized bed (FB). Loadings of up to 40% were successfully formulated, showing significant improvement in the dissolution profile. Additional improvement in dissolution was achieved by mild milling of the impregnated drug product. Moreover, co-impregnation of the API with an FDA approved additive showed significant further improvement in dissolution profile, making our formulation comparable to one of Fenofibrate’s patented market formulations (TriCor, 45mg). Other benefits of our impregnation method include: high blend uniformity independent on API nature or loading, excellent flow properties of the impregnated powder (no need for more additives), elimination of several unit operations from drug substance and drug product development.