pre-cooling, milling and intermediate cooling steps with liquid nitrogen. In the pre-cooling step, the mill was cooled down to the temperature of -70 oC using a liquid nitrogen flow through the mill jacket. Milling was performed at a vibrational frequency of 25 Hz for 10 s. Intermediate cooling between two consecutive milling cycles was performed at a vibrational frequency of 5 Hz for 40 s. Each milling cycle is defined as the milling step and the intermediate cooling step. The effect of milling time on particle size reduction and surface energy was studied by varying the number of milling cycles (n=1, 3, …, 12). Post milling, samples were collected and stored in the glass vials for further characterisation and processing. Silanisation of Milled Mefenamic Acid Recrystallised mefenamic acid crystals and milled mefenamic acid powders were silanised using a protocol reported in the literature (). For milled mefenamic acid, powders were silanised after milling. In a typical process, 500 mg of mefenamic acid powder was added to a 50 mL 5% (v/v) solution of dichlorodimethylsilane in cyclohexane. The mixture was refluxed at 80 oC for 24 hours. Then, the reaction mixture is allowed to cool down to room temperature and filtered using general-purpose laboratory filter paper (Whatman, UK) followed by drying in a vacuum oven at 80 oC for 4 hours. Post silanisation, the silanised mefenamic acid powders were stored in a glass vial at ambient conditions. Surface Energy Analysis Surface Energy Analyser (SEA, Surface Measurement Systems Ltd., London, UK) was used for surface energy heterogeneity characterisation. Mefenamic acid powders were packed in pre-silanised iGC columns (4 mm (internal diameter) × 300 mm (height)) (Surface Measurement Systems Ltd., London, UK). The powder bed was contained with silanised glass wool at both ends to avoid powder bed movement. Approximately 300 mg of processed mefenamic acid material was packed into each column. The columns were conditioned using the SEA equipment for 2 hours at 30oC with helium purge at 10 sccm . Following the pre-treatment, pulse injection measurements were performed at 30 oC. Methane
pre-cooling, milling and intermediate cooling steps with liquid nitrogen. In the pre-cooling step, the mill was cooled down to the temperature of -70 oC using a liquid nitrogen flow through the mill jacket. Milling was performed at a vibrational frequency of 25 Hz for 10 s. Intermediate cooling between two consecutive milling cycles was performed at a vibrational frequency of 5 Hz for 40 s. Each milling cycle is defined as the milling step and the intermediate cooling step. The effect of milling time on particle size reduction and surface energy was studied by varying the number of milling cycles (n=1, 3, …, 12). Post milling, samples were collected and stored in the glass vials for further characterisation and processing. Silanisation of Milled Mefenamic Acid Recrystallised mefenamic acid crystals and milled mefenamic acid powders were silanised using a protocol reported in the literature (). For milled mefenamic acid, powders were silanised after milling. In a typical process, 500 mg of mefenamic acid powder was added to a 50 mL 5% (v/v) solution of dichlorodimethylsilane in cyclohexane. The mixture was refluxed at 80 oC for 24 hours. Then, the reaction mixture is allowed to cool down to room temperature and filtered using general-purpose laboratory filter paper (Whatman, UK) followed by drying in a vacuum oven at 80 oC for 4 hours. Post silanisation, the silanised mefenamic acid powders were stored in a glass vial at ambient conditions. Surface Energy Analysis Surface Energy Analyser (SEA, Surface Measurement Systems Ltd., London, UK) was used for surface energy heterogeneity characterisation. Mefenamic acid powders were packed in pre-silanised iGC columns (4 mm (internal diameter) × 300 mm (height)) (Surface Measurement Systems Ltd., London, UK). The powder bed was contained with silanised glass wool at both ends to avoid powder bed movement. Approximately 300 mg of processed mefenamic acid material was packed into each column. The columns were conditioned using the SEA equipment for 2 hours at 30oC with helium purge at 10 sccm . Following the pre-treatment, pulse injection measurements were performed at 30 oC. Methane
48%20-%20Revised%20Manuscript%20-%20Decoupling%20the%20contribution%20of%20surface%20energy%20and%20surface%20area%20on%20the%20cohesion%20of%20pharmaceutical%20powders.docx