Purpose: Spray dried amorphous solid dispersions (SDDs) are well utilized for enhancing bioavailability of poorly water soluble drug substances. To maintain safety, efficacy and shelf-life, the SDD drug product must be physically and chemically stable, achieve the target product profile in the gastrointestinal tract and have robust manufacturability. To achieve physical stability and performance, the SDD intermediate often needs to contain a high fraction of polymer to stabilize the high energy, amorphous state of the drug substance. To achieve performance and manufacturability, the drug product (e.g. tablet) typically needs to contain a high fraction of non-gelling tableting excipients. Incorporation of these additional materials in the SDD drug product can result in significant dilution of the drug substance and therefore result in high pill burden. The aim of this work is to use a novel architecture to increase the percentage of a low glass transition temperature (Tg), rapidly-crystallizing model drug in a tablet compared to a benchmark formulation. In this novel approach, a drug substance is spray dried with the high Tg dispersion polymer, PMMAMA, to facilitate high drug loading in the SDD, while still maintaining physical stability. Because PMMAMA does not typically extend supersaturation in solution, a concentration sustaining polymer (CSP) is granulated with the SDD for incorporation into the tablet.
Methods: Erlotinib free base was spray dried with PMMAMA (Eudragit L100®, Evonik, Essen, Germany) at a ratio of 65:35 Erlotinib:PMMAMA to form an SDD. The SDD was then combined with the CSP, hydroxypropyl methyl cellulose acetate succinate (HPMCAS) (AQOAT® H grade, Shin-Etsu Chemical Co., Tokyo, Japan), and tableting excipients via a dry granulation process at a ratio of either 0.8:1 or 2:1 CSP:Erlotinib to create two different tablet formulations. A benchmark SDD containing the CSP (HPMCAS H grade) as the dispersion polymer was spray dried at a ratio of 35:65 Erlotinib:HPMCAS. This SDD was combined with tableting excipients via a dry granulation process to create a benchmark tablet formulation. For both the new architecture and the benchmark approaches, drug loading in the SDD and SDD loading in the tablet were maximized to achieve physical stability and performance based upon previous studies. SDDs were stored under elevated temperature and humidity conditions (50 ◦C and 75% RH) for up to four weeks to assess physical stability. Before and after storage SDDs were 1) analyzed to confirm they were homogeneous as evidenced by a single Tg using a modulated differential scanning calorimeter (mDSC), 2) assessed for the presence of crystals and changes in particle shape and morphology using scanning electron microscopy (SEM) and 3) analyzed using powder X-ray diffraction (PXRD) to confirm they were amorphous. Tablets of SDDs were evaluated for 1) dissolution performance in a gastric to intestinal transfer dissolution test in a USP 2 apparatus and 2) disintegration performance in a USP disintegration apparatus.
Results: Tablets created using the novel architecture achieved active loadings either 2-fold or 1.5-fold greater than tablets created using the benchmark formulation strategy, when CSP was combined in the tablet at a ratio of 2:1 or 0.8:1, respectively. Performance and stability were comparable to the benchmark for both tablet formulations with respect to in vitro disintegration performance (29% or 16% faster than benchmark), in vitro dissolution performance (AUC values in simulated intestinal buffer 77% or 112% of benchmark) and SDD physical stability (both SDDs stable after 4 weeks).
Conclusion: Strategically combining two different functional polymers in a tablet versus using a single polymer to maintain physical stability and sustain supersaturation in solution enabled increased loading of amorphous Erlotinib in a tablet, while still maintaining comparable SDD physical stability and in vitro dissolution performance. This strategy may be useful for decreasing tablet size and/or number of dosage units for drug candidates requiring an amorphous form of the drug to achieve the target product profile in vivo.
Nishant Biswas– Lonza Pharma & Biotech
Stephanie Buchanan– Lonza Pharma & Biotech
Kimberly Shepard– Lonza Pharma & Biotech
Adam Smith– Lonza Pharma & Biotech
Aaron Stewart– Lonza Pharma & Biotech
Christopher Craig– Lonza Pharma & Biotech
Michael Morgen– Lonza Pharma & Biotech
David Vodak– Lonza Pharma & Biotech