Towards scientific manufacturing: The effects of shear rate, strain, and composition on the properties of blends and tablets.

摘要

This dissertation aims at understanding the effects of formulation (type of excipient, APAP grade, lubricant concentration) and processing conditions (shear rate and strain) on the following properties of pharmaceutical blends and tablets: (1) Degree of Active Pharmaceutical Ingredient (API) agglomeration and homogeneity. (2) Density, flowability, and hydrophobicity of lubricated formulations. (3) Tablet hardness. Another aim is to develop a method to assess the API de-agglomeration in blenders, when only a small fraction of the blend is sampled.;The blend properties examined are those that impact on the quality of the product: blend density determines the amount of powder that fills the tablet dies, blend hydrophobicity determines the dissolution properties of tablets, powders, or capsules, and API agglomeration determines the probability of having out-of-specification products.;The experimental method uses a shear cell where shear rate and strain can be controlled. The different blend properties are measured using suitable analytical techniques.;For the assessment of API de-agglomeration in blenders, a numerical method is developed to design sampling protocols that detect and characterize agglomerates with a degree of statistical confidence. The results show that: (1) The degree of API agglomeration decreases as a function of strain, and independently of shear rate. A coarser API presents a significantly smaller degree of agglomeration than a finer API. De-agglomeration proceeds at very similar rates in different excipients. (2) Blend hydrophobicity increases steadily as a function of strain and lubricant concentration. Larger shear rates increase hydrophobicity even further. Tapped density of lubricated blends increases as a function of strain until reaching a maximum value, independently of shear rate. The flowability of lubricated blends is enhanced but independently of strain and shear rate they have been exposed to. (3) The tablet crushing hardness is a function of the strain applied to lubricated blends and independent of the shear rate.;The statistical method used to detect and characterize API agglomerates in blenders yields concentration profiles that compare very well to the experimental concentration profile. This procedure validates the parameters that describe the agglomerate population (with a normal distribution of sizes) in a blend.