Issue link: https://www.e-digitaleditions.com/i/1218534
Tablets & Capsules March 2020 11 formulations. This increases the reliability of the pro- cess and improves efficiency because it helps to enable better early decisions about whether to develop an API. Case study The following case study demonstrates this compre- hensive approach for generating solid dosage forms for To improve a drug's kinetic solubility, formulators commonly use amorphous dispersions (amorphous API in a polymer matrix). Techniques to convert a crystal- line API to amorphous form include spray dried disper- sion (SDD) and hot melt extrusion (HME). Determin- ing the right polymer to keep an API in a shelf-stable, non-crystalline form is traditionally a lengthy evalua- tion process that requires gram quantities of API. The ability to address solubility issues early can save costs and time and may rescue potentially life-saving com- pounds during development. This article describes a streamlined approach for quickly finding the best formulation while minimizing the amount of API required. The approach uses small- scale studies that test multiple excipient matrices in parallel and only require milligram quantities of API. These screenings prove to be a good indication of SDD or HME results. Once the screenings identify promis- ing excipient matrices, they are scaled up to make spray dried dispersions and/or extrudates and combined with other solubilizing techniques to make the API into a usable dosage form to be studied in animals. This approach integrates formulation and manufac- turing with discovery, so parallel in vivo drug metabo- lism and pharmacokinetics (DMPK) studies can quickly give insights to the bioavailability of the candidate API Table 1 API solubility in various solvents (mg/ml) Solvent Initial After 16 hours THF < 5 < 5 Dichloromethane (DCM) 3 3 Acetone < 5 < 5 Methanol < 2.5 < 2.5 Ethyl acetate < 5 < 5 Ethanol 3 < 3 25:75 Methanol:DCM 5 < 5 50:50 Methanol:DCM 5 < 5 90:10 Methanol:DCM < 2.5 < 2.5 90:10 THF:ethanol 5 < 5 85:10:5 THF:ethanol:water 5 5 Figure 1 Micro-evaporation screening method to identify solubility enhancing polymer matrix API concentration (μg/ml) 70 60 50 40 30 20 10 0 Time (minutes) API 25:75 API:Kollidon VA64 25:75 API:Kollidon VA64 + 1% TPGS 25:75 API:HPMCAS-MF 12 0 2 4 6 8 10 API + polymer solution Dosing vehicle Dry