(586ah) Novel Approach for Stabilizing Physical Form of a Drug Substance in Tablet Formulations

PURPOSE

The objective was to develop a commercially viable tablet dosage form for
a BCS class II oncology compound.  The key challenge, in addition to low
solubility (<1 ug/ml), was the tendency of the anhydrous drug substance to readily
convert to a hydrate (a_w 0.26 - 0.36).  The formation
of the lower solubility hydrate form during shelf-life led to a 2-3 fold
decrease in the oral bioavailability.  The specific aim was to kinetically
stabilize the anhydrous form of the drug in the tablets and achieve superior bioavailability.

METHODS

The kinetics of the anhydrate
→ hydrate transition were mapped for aqueous systems containing a series
of polymeric excipients.  Tablets were manufactured using the dry granulation
and the wet granulation approaches.  Further, the choice of binder and the mode
of binder addition (dry, solution, or foam) were evaluated for the wet
granulation process.   Particle size effect (0.3 - 70 um) on bioavailability
was also evaluated.

RESULTS

The anhydrous form of the API when
suspended in aqueous medium converted to the hydrate in <24 hrs.  Aqueous
solutions containing cellulosic polymers such as hydroxypropyl cellulose (HPC, 0.1
- 5%w/w) successfully inhibited the form conversion.  The kinetically
stabilized suspensions showed a 2-fold improvement in bioavailability as
compared to particle size reduction approach, emphasizing the importance of
form control.  The tablets containing HPC manufactured by the dry granulation
process underwent rapid form conversion under high humidity conditions, attributable
to ineffective distribution of HPC in the formulation.  In contrast, the
tablets prepared using wet granulation process using aqueous HPC solution as a
binder showed a pronounced improvement in physical stability.  The stability
was further enhanced when HPC was added in as foam
during granulation. The foam technology (Dow) led to a more uniform
distribution of the stabilizer within the tablet matrix.  The resultant tablets
were stable under stressed conditions (40C/75%rh) for >3 months, and provided
significantly superior bioavailability in humans as compared to formulations
containing the hydrate form.

CONCLUSION

The API form conversion in drug
product was successfully inhibited by incorporating a polymeric stabilizer in
the formulation matrix.  Generally, a dry granulation unit operation is
utilized for processing of materials that are sensitive to moisture.  This work
demonstrated that effective distribution of the polymeric stabilizer in the API
microenvironment via the aqueous foam granulation approach provided a drug
product with superior physical stability.  The approach enabled manufacture of tablets
having enhanced bioavailability and extended shelf-life.