(666e) Formulation and Manufacture of Pharmaceuticals by Fluidized Bed Impregnation of APIs Onto Porous Carriers

Approximately
65% of all prescription drugs are manufactured as solid dosage forms, which
include tablets and capsules. In most of these cases the final formulation is a
physical blend consisting of an excipient and an active pharmaceutical
ingredient (API), which preferably is homogeneously distributed throughout the
excipient. Mixing of powders almost always poses great challenges to
formulators, especially in cases where there is a pronounced difference between
the powders' particle size, flowability, surface properties, etc. These
challenges often translate into un-homogeneously distributed API. For very
potent drugs the amount of API in the solid dosage form can be as low as 0.1%
by weight. This very low API loading poses one of the biggest problems in
pharmaceutical product development: the control of blend uniformity. Low API content
variability in the blend or high blend homogeneity are highly desired and
strictly enforced by the U.S. Food and Drug Administration (FDA). In the
commonly available approaches for blend uniformity control (direct blending,
wet/dry granulation) as the API concentration decreases, the variability of the
blend increases; this makes it very difficult to meet FDA's requirements for
low drug loadings. Therefore a process or method that is able to tightly
control API variability in blends, regardless of drug loadings or physical
properties of the API, has become very desirable.

In this paper we
describe a novel method for the formulation and manufacture of pharmaceuticals
that circumvents all difficulties associated with powder mixing and all negative
consequences associated with such blends. The method involves fluidized bed
(FB) impregnation of APIs onto porous carriers. The main idea behind this
method is the deposition of the drug material inside the excipient particles.
This impregnation is achieved by spraying an API solution onto porous excipient
in a fluidized bed, achieving what could be seen as continuous wet impregnation
and drying process. Overall quality of resulting impregnated blend depends on
process parameters such as product drying temperature and spray rate of API
solution.

Impregnated excipients exhibit one main difference when compared to
regular blends. That is, the API is located inside carrier particles which
results in powder properties that are almost identical to those of the pure excipient, thus eliminating API/excipient
segregation. Combining all this with the facts that FBs exhibit very good
powder mixing and that each excipient particle is impregnated "one at a
time", results in highly homogeneous API distribution. We also discovered
that consequent milling of the impregnated excipient
further improves blend uniformity. Included table below shows blend uniformity
(as % RSD) for impregnated blends (milled and um-milled) of various loadings
using acetaminophen (APAP) as the active pharmaceutical ingredient.

Other advantages
of proposed formulation method include: simple and efficient (eliminates
several unit operations from drug substance and drug product development), safe
(minimizes API powder handling), depends only on excipient's
properties (independent of API nature).