De-risking pharmaceutical tablet manufacture through process understanding, latent variable modeling, and optimization technologies.

In pharmaceutical tablet manufacturing processes, a major source of disturbance affecting drug product quality is the (lot-to-lot) variability of the incoming raw materials. A novel modeling and process optimization strategy that compensates for raw material variability is presented. The approach involves building partial least squares models that combine raw material attributes and tablet process parameters and relate these to final tablet attributes. The resulting models are used in an optimization framework to then find optimal process parameters which can satisfy all the desired requirements for the final tablet attributes, subject to the incoming raw material lots. In order to de-risk the potential (lot-to-lot) variability of raw materials on the drug product quality, the effect of raw material lot variability on the final tablet attributes was investigated using a raw material database containing a large number of lots. In this way, the raw material variability, optimal process parameter space and tablet attributes are correlated with each other and offer the opportunity of simulating a variety of changes in silico without actually performing experiments. The connectivity obtained between the three sources of variability (materials, parameters, attributes) can be considered a design space consistent with Quality by Design principles, which is defined by the ICH-Q8 guidance (USDA 2006). The effectiveness of the methodologies is illustrated through a common industrial tablet manufacturing case study.

Osmotic capsules: A universal oral, controlled-release drug delivery dosage form.

An osmotic, oral, controlled-release capsule is described. This capsule provides drug delivery at fixed delivery rates (T(80%)=6 or 14h) independent of drug properties (e.g., solubility) or drug loading, thereby allowing rapid development of investigational or commercial drugs, especially for proof-of-concept type clinical studies. The capsule body and cap are prepared with cellulose acetate and polyethylene glycol in acetone and water using high density polyethylene molds as templates and a conventional tablet pan coater. After the shells are removed from the molds manually, a laser hole is drilled in the end of the capsule body. The drug is introduced as a shaped tablet admixed with polyethylene oxide. A "push" tablet consisting of high molecular weight polyethylene oxide, microcrystalline cellulose, and sodium chloride is also inserted into the capsule body. The capsule halves lock together due to ridges, alleviating the need for a banding operation.

Measurement of the surface energy of lubricated pharmaceutical powders by inverse gas chromatography.

The objective of the study was to determine whether lubrication of pharmaceutical powders with magnesium stearate (MgSt) results in a change in the surface energy of the powder, and to assess whether surface energy changes, if any, are correlated to lubricant concentration and blend time. The surface energies of microcrystalline cellulose (MCC), lactose, and blends of each material with MgSt, prepared at a range of concentrations and blending times were measured using inverse gas chromatography. The physical distribution of MgSt in the blend was mapped by energy dispersive spectrometry. Overall, there was a reduction in the dispersive surface energy of MCC-MgSt blends with increase in MgSt concentration, that was attributed to increasing coverage of the high-energy sites on microcrystalline cellulose by magnesium stearate. MgSt concentration had a larger effect on dispersive energy than the blending time of the powder with lubricant. X-ray maps of blend samples indicated a heterogeneous distribution of the lubricant in the blend and on the excipient particles. Measurement of the specific component of surface energy indicated that MgSt interacts with excipient powders through non-specific forces rather than acid-base interactions. No distinction among lactose-MgSt blends could be made on the basis of dispersive energy because of similar surface energies of the native materials.

Polydisperse powder mixtures: effect of particle size and shape on mixture stability.

The effect of the shape and size of the components on the stability of mixtures was evaluated in binary mixtures of drug and carrier. Aspirin was used as model drug; spray-dried lactose and microcrystalline cellulose were used as carriers. The coefficient of variation (CV) of the drug in the mixture at various time intervals during mixing was used as a measure of homogeneity. The stability of mixtures was assessed under conditions that were conducive to segregation-in this case, prolonged mixing. The pattern of change in CV with time was analyzed in terms of convective, shear, and diffusive mixing stages. The variation resulting from a change in the shape of the carriers was smaller than that resulting from size differences. The segregation rate constant, calculated on the assumption of a first-order mixing process, was found to be larger in mixtures having components of different shape than in mixtures having components of similar shape. In mixtures of micronized drug and carrier, the pattern of change in the CV of drug with mixing time was attributed to the distribution of agglomerates of micronized drug during convective mixing, followed by shearing of agglomerates and, finally, the distribution of the primary particles during diffusive mixing. Mixtures of non-cohesive powders of similar size and shape behaved like random mixtures of non-interacting components.

Effect of magnesium stearate on the content uniformity of active ingredient in pharmaceutical powder mixtures.

The objective of this study was to determine the effect of magnesium stearate on the physical stability of polydisperse powder mixtures. The effects of concentration of magnesium stearate and the time of lubrication of mixtures with magnesium stearate on the content uniformity of the active ingredient in the mixtures were evaluated in a model mixture of lactose and aspirin. These effects were compared in a random mixture of non-interacting components and a mixture based on particle interaction. A statistical model that adequately described the relationship between the factors examined and the response was generated. The model indicated the presence of an interaction between magnesium stearate concentration and lubrication time. At a given concentration of magnesium stearate, there was a significant reduction in the content uniformity of aspirin as the time of lubrication of the mixture with magnesium stearate was increased. This effect was larger in mixtures based on particle interaction than in random mixtures of non-interacting components.