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.