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12 March 2020 Tablets & Capsules further improved API solubility. We then used the poly- mers with the best dissolution performance for SDD. Differential scanning calorimetry screening method for HME polymer selection For APIs with thermal stability above 200°C, HME is a cost-effective method for making amorphous disper- sions. To identify the ideal polymer for the HME tech- nique, we used a different screen. Differential scanning poorly soluble compounds. In this case study, a client had an oral antibacterial API candidate with very poor solubil- ity and needed to develop an immediate-release tablet for Phase 1 clinical trials. By evaluating a broad set of solubili- zation approaches and correlating those formulations with in vivo and in vitro data, BioDuro developed an optimal and clinically-relevant formulation, which enabled the program to move forward into clinical trials. The API had a strong crystal structure and a very high melting temperature of 262°C. The first chal- lenge was to determine the best solvent system to use, with the aim of achieving 10 mg/ml solubility. The API was extremely hydrophobic, with solubility of only 8 μg/ml in water, and was difficult to dissolve even in organic solvents. As shown in Table 1, the maximum solubility achieved was 5 mg/ml, using a 3-component solvent system containing tetrahydrofuran (THF), eth- anol, and water (85:10:5) and requiring a specific order of addition for the solvent components. The second challenge was stability. Even after making the API amorphous, we learned that it would immediately start to crystallize again and lose solubility in any formu- lation with more than 25 percent API. Creating a usable drug formulation with a stable shelf life required the right ratio of API and excipients to keep the API amorphous for at least two years. We used two small-scale screening methods—micro-evaporation and differential scanning calorimetry—to efficiently determine the best amorphous dispersion formulations for the API. Micro-evaporation screening method for SDD polymer selection We started with micro-evaporation studies to iden- tify the polymer matrix that best enhanced solubility. Micro-evaporative dispersions present an innovative and efficient solution to overcoming low API solu- bility. This method requires only milligrams of API, and allows parallel evaluation of multiple approaches, including different excipients, proportions, and con- centrations. Micro-evaporation is a small-scale screen that is a good predictor of SDD formulation. Results from micro-evaporation studies then can be leveraged into downstream development of the most suitable for- mulation to put on a spray dryer. The protocol for the micro-evaporation screen starts with preparing API-polymer mixtures in solvent and drying them in a speedvac concentrator. We resus- pended the dried films in pH 6.8 phosphate buffer by vortexing and transferred test samples to 96-well plates to determine dissolution performance by UV absor- bance. Figure 1 shows this workflow and the results for API alone, compared to three candidate matrices: 25:75 API:HPMCAS-MF, 25:75 API:Kollidon VA64, and 25:75 API:Kollidon VA64 with 1 percent TPGS. All three matrices showed multi-fold solubility improvement over the API alone. Kollidon VA64 is a better polymer backbone for the matrix compared to HPMCAS-MF, and addition of the surfactant TPGS Formulation Heat capacity of API melt peak (J/g) API alone 96.61 25:75 API:Kollidon VA64 3.253 50:50 API:Kollidon VA64 9.320 25:75 API:HPMCAS-MF 38.92 50:50 API:HPMCAS-MF 57.86 25:10:65 API:TPGS:Kollidon VA64 4.049 50:10:40 API:TPGS:Kollidon VA64 13.75 Table 2 Heat capacity comparison of different formulations in heat-cool-heat DSC analysis Figure 3 X-ray diffraction patterns of API versus amorphous dispersions 1.5e+005 1.0e+005 0.5e+004 0.0e+000 10 20 30 40 Theta/2-Theta (deg) Intensity (CPS) GC-072 SDD 10:90 API:VA64 GC-072 SDD 10:10:80 API:TPGS:VA64 GC-072 API (AMRI) Figure 2 Non-sink dissolution study of formulations in fasted-state simulated intestinal fluid (pH 6.5 FaSSIF) Concentration (μg/ml) 1,200 1,000 800 600 400 200 0 Time (minutes) 25:10:65 API:TPGS:Kollidon VA64 HME 25:10:65 API:TPGS:Kollidon VA64 SDD API 70 0 20 30 10 40 50 60