Kostas Saranteas

Practical methods for improving flow properties of active pharmaceutical ingredients

Objective: The essential aim of this article is to develop effective methods for improving the flow properties of active pharmaceutical ingredients (APIs) without requiring particle size or shape modification. Methods: The ‘formulation’ approach used here focuses on enhancing flow properties of three chemically different drug powders (micronized acetaminophen, levalbuterol tartrate, and didesmethylsibutramine tartrate) by using small amounts of lubricants, glidants, and other additives, both individually and in combination. Additives are intimately mixed using a laboratory-scale V-blender with an intensifier bar. Flow index, dilation, and electrical impedance were measured for a total of 24 blends. Results: The flow behavior of all three APIs improved with the addition of these additives. Relative effectiveness of different additive combinations displayed remarkable consistency for all three APIs. Simultaneous presence of SiO2, MgSt, and talc led to substantial decreases in cohesiveness, causing major improvements in flowability of powder. All three properties showed a very tight correlation. Conclusions: Drug powders with improved flow were found to exhibit low dilation and low impedance values. A common linear correlation between flow index and impedance and also between dilation and impedance was observed for all three APIs, indicating that electric properties play a substantial role in the cohesivity of all three APIs, and suggesting the presence of a common mechanism for the emergence (and mitigation) of cohesive phenomena.

Improvement of tablet coating uniformity using a quality by design approach.

A combination of analytical and statistical methods is used to improve a tablet coating process guided by quality by design (QbD) principles. A solid dosage form product was found to intermittently exhibit bad taste. A suspected cause was the variability in coating thickness which could lead to the subject tasting the active ingredient in some tablets. A number of samples were analyzed using a laser-induced breakdown spectroscopy (LIBS)-based analytical method, and it was found that the main variability component was the tablet-to-tablet variability within a lot. Hence, it was inferred that the coating process (performed in a perforated rotating pan) required optimization. A set of designed experiments along with response surface modeling and kriging method were used to arrive at an optimal set of operating conditions. Effects of the amount of coating imparted, spray rate, pan rotation speed, and spray temperature were characterized. The results were quantified in terms of the relative standard deviation of tablet-averaged LIBS score and a coating variability index which was the ratio of the standard deviation of the tablet-averaged LIBS score and the weight gain of the tablets. The data-driven models developed based on the designed experiments predicted that the minimum value of this index would be obtained for a 6% weight gain for a pan operating at the highest speed at the maximum fill level while using the lowest spraying rate and temperature from the chosen parametric space. This systematic application of the QbD-based method resulted in an enhanced process understanding and reducing the coating variability by more than half.

Analysis of Pharmaceutical Tablet Coating Uniformity by Laser-Induced Breakdown Spectroscopy (LIBS)

A laser-induced breakdown spectroscopy-based analytical methodology is developed to study tablet coating variability in pharmaceutical tablets. The method quantifies the amount of coating on a tablet by assigning an average coating thickness score to it. When tested using samples with different amounts of coating, the coating thickness scores showed direct correlation to the weight gain of the tablet, hence validating the analytical method. The relative significance of the processing parameters and the components of variability were computed using statistical techniques. The sampling frequency of laser shots was found to have no significant effect. The effect of the position of the laser pulse on the tablet surface was found to be significant; however, it was determined that this effect was due to the tablet curvature, which resulted in the laser optical path to intersect the coating diagonally. The variability between batches (lots) manufactured under the same processing conditions was not significant. The largest avoidable source of variability was the tablet-to-tablet component, possibly indicating the inadequate mixing performance of the coating device.

Dynamic Optimization of a Batch Pharmaceutical Reaction using the Design of Dynamic Experiments (DoDE): the Case of an Asymmetric Catalytic Hydrogenation Reaction

Abstract The present research work aims to demonstrate the effectiveness of the new methodology of Design of Dynamic Experiments (DoDE) in optimizing an important pharmaceutical reaction. An easily developed response surface model (RSM) is used instead of a hard to develop knowledge-driven process model. The DoDE approach allows the experimenter to introduce dynamic factors in the design, which during the RSM optimization are treated as all the other factors, simplifying the analysis significantly, leading to the rapid optimization of batch processes with respect to time-varying decision variables. The DoDE approach enables the discovery of optimal time-variant operating conditions that are better than the optimal time-invariant conditions discovered by the classical Design of Experiments (DoE) approach. In the present case of the asymmetric catalytic hydrogenation, 24 experiments are conducted for the DoDE approach and the best run results in a 45% improvement comparing to the best run of 17 runs of the DoE approach. This is achieved by applying a decreasing temperature profile during the batch reaction. Optimization of the economic performance index of the process through the respective response surface models defines an optimum operation. The DoDE optimum operation is better than the respective one through the DoE. The DoDE advantage increases as the required quality level for the final product is higher. For the medium quality, the DoDE approach results in an improvement of 30% over the DoE one.

Factors affecting on-line estimation of diastereomer composition using Raman spectroscopy

This paper addresses the estimation of fractional composition of two diastereomers during crystallization. The estimation is obtained through a Partial Least Square (PLS) model that utilizes on-line Raman spectroscopy and additional process information such as temperature and slurry density. Several PLS models are developed that incorporate conditions that either neglect or account for variability in the additional process variables. It is argued that the model that incorporates both temperature and slurry density is the most accurate. Copyright