The powder flow and compact mechanical properties of sucrose and three high-intensity sweeteners used in chewable tablets.

The physical, flow, and mechanical properties of four common pharmaceutical sweeteners were measured to assess their relative manufacturability in solid dosage formulations. Sucrose, acesulfame potassium (Sunett), saccharin sodium, and aspartame were evaluated to determine significant differences in particle shape, size distribution, and true density. Powder flow and cohesivity as well as compact mechanical properties such as ductility, elasticity, and tensile strength were measured and found to be noticeably different. Among these sweeteners, sucrose and acesulfame potassium demonstrated excellent flowability and marginal mechanical property performance relative to over 100 commonly used pharmaceutical excipients evaluated in the authors' laboratory. Saccharin sodium and aspartame demonstrated poor flowability and superior compact strength relative to sucrose and acesulfame, despite their noticeably higher brittleness. These data suggest that careful selection of an appropriate sweetener is warranted in obtaining desirable process and tableting robustness, particularly if sweetener loading is high. Detailed descriptions of each material property and recommendations for sweetener selection in formulation development are included.

Comparison of the mechanical properties of the crystalline and amorphous forms of a drug substance.

PURPOSE: To better understand the influence of long-range molecular order on the processing characteristics of an active pharmaceutical ingredient (API). METHODS: Crystalline and amorphous samples of a model drug substance were isolated and their "true" density, crystallinity, melting point, glass transition temperature, particle size distribution, and powder flow characteristics determined. Compacts of a standard porosity were manufactured from each form and their dynamic indentation hardness, quasi-static indentation hardness, tensile strength and "compromised tensile strength" determined. X-ray powder diffraction was used to confirm that no changes were induced by compact formation or testing. RESULTS: The crystalline and amorphous forms of the drug substance had relatively high melting and glass transition temperatures (approximately 271 and 142 degrees C, respectively) and were physically and chemically stable under the conditions of the testing laboratory. Consistent with this there was no evidence of crystallinity in the amorphous samples or vice versa before, during or after testing. The two API lots were effectively equivalent in their particulate properties (e.g. particle size distribution), although differences in their particle morphologies were observed which influenced powder flow behavior. The compacts of the bulk drug samples exhibited moderate ductility, elasticity, and strength, and high brittleness, in keeping with many other drug substance samples. A significantly greater compression stress was required to form the compacts of the crystalline material, and these sample materials were more ductile, less brittle and less elastic than those made from the amorphous API. There were no major differences in the tensile strength or the viscoelasticity of the compacts made from the crystalline and amorphous samples. CONCLUSIONS: The mechanical properties of compacted amorphous and crystalline samples of a drug substance have been measured and the contributions due to the molecular ordering of the crystalline form proposed. Small but significant differences in the mechanical properties were noted which could potentially affect the processing performance of API.

Examining the impact of excipient material property variation on drug product quality attributes: a quality-by-design study for a roller compacted, immediate release tablet.

A quality-by-design study examining the impact of variability in excipient material properties on the quality attributes of an immediate release tablet was performed. A literature review and risk analysis identified particle size of microcrystalline cellulose (MCC), spray-dried lactose (SDL), and magnesium stearate (MgSt), and polymorph and specific surface area of MgSt as potential high-risk material properties. The following results were obtained with laboratory-scale processing equipment: (1) a 32-µm increase in d(50) (mean particle diameter) of MCC and SDL led to a ∼ 30-µm increase in blend and granulation d(50) and a statistically significant increase in the blend and granulation flow function coefficients, and (2) a 32-µm increase in d(50) of MCC and SDL, a 4.4 m(2)/g increase in the surface area, and a 19-µm decrease in the particle size of MgSt yielded an 18%-28% increase in ribbon tensile strength and tablet hardness. Confirmatory experiments with kilo-scale equipment showed impact of excipient variability on granulation particle size and tablet hardness was ∼ 50% smaller. Although the impact of these differences on overall manufacturability and performance of the tablets examined here were deemed low, the presence of statistically significant effects supports examining excipient variability as part of the design and control strategy of new drug products.