Since the API is not handled in large quantities and Phase
I dosage form requirement is typically a couple of thousand
dosage units, clinical supplies can be manufactured using bench-top, small-scale equipment that uses manual or
semi-automated process. Depending on the API dosage and
drug loading, these parameters may or may not be critical
to manufacturing. From a chemical standpoint, we need to
understand the choice of the right and stable polymorph,
its chemical stability, hygroscopicity and forced degradation
profile. The dose range of the API is a critical parameter in
consideration of the choice of the dosage form that can be
The dose of the API, the particle size, density and flow
are critical in successfully filling the accurate amount of
API in a capsule. Larger doses with a low bulk density and
poor flow characteristics could pose a challenge as the cap-sule-filling mechanism may not be able to densify, tamp or
pack a low bulk density powder in the capsule. When API is
blended with a minimum number of excipients such as fillers and flow aids, the blend is better handled by equipment
designed for capsule filling of a better flowing material.
Capsule fillers that use a plate of 50, 100 or 300 capsules
could be a better choice for filling a blend of API with excipients such as fillers, disintegrants and flow-aids as this
mechanism cannot fill partial capsules. Another advantage
of adding fillers is that tamping helps to densify and pack
the low-density blend into the volume of the capsule. These
types of capsule fillers are popular as the small number of
capsules required for a short clinical study can be speedily
manufactured. Several thousands of unit dose capsules can
be manufactured using these types of encapsulators with a
reasonable weight variation.
POWDER IN A BOTTLE
The process commonly referred to as powder for re-
constitution is another approach for a quick manufacture
A robust solid-state characterization of the API at an early
stage helps drug developers better understand the properties
of the API and the effect they have on drug behavior, espe-
cially on uniform particle size and distribution, solubility,
stability, in-vitro dissolution and bioavailability. A complete
knowledge of the relevant physicochemical properties is es-
sential for effective formulation development decisions.
PHASE I DOSAGE FORM DEVELOPMENT AND
The most commonly developed solid oral dosage forms for
a Phase I clinical study are:
• Neat API in a capsule.
• Blend in a capsule.
• Powder in a bottle.
• Liquid-filled hard shell capsule/softgel if it is a lipid-based
Only in special cases is a tablet dosage form developed for
an early Phase I clinical study. At this early stage, it is es-
sential to develop a dosage form that brings speed and flexi-
bility in dosing for a quick proof of concept as API is available
in very small quantities and there is seldom an opportunity
to perform elaborate development work to optimize a formu-
lation and process.
In addition, since the duration of the clinical study is often short, the stability of the dosage form required should be
enough to cover the clinical program and justify the suitability
of the clinical material. The physical properties of the API critical in developing the above-described “Quick to Clinic™” dosage forms are – particle size, bulk and tapped density and, to a
certain extent, flow, cohesiveness and static behavior.
API Properties – Risk
Assessment for Effective
Phase I Dosage form
n Anil Kane, Ph.D., Executive Director, Global Head of Formulations, Pharmaceutical Development