Design of Experiments (DoE)-based approach for improvement of dry mixing processes in the production of low-dose Alprazolam tablets using Raman spectroscopy for content uniformity monitoring

Makraduli, Liljana and Makreski, Petre and Makraduli, Filip and Spirevska, Irena Slaveska and Stoimenova, Tanja Bakovska and Todevska, Elena Lazarevska and Piponski, Marjan and Anevska, Maja and Dodov, Marija Glavas and Crcarevska, Maja Simonoska and Mladenovska, Kristina and Goracinova, Katerina and Geskovski, Nikola (2023) Design of Experiments (DoE)-based approach for improvement of dry mixing processes in the production of low-dose Alprazolam tablets using Raman spectroscopy for content uniformity monitoring. Archives of Pharmacy, 73 (1). pp. 35-61.

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Abstract

A low-dose tablet formulation, containing a potent benzodiazepine derivative Alprazolam
was developed, considering the achievement of appropriate content uniformity of the active
substance in powder blends and tablets as a major challenge. Two different types of lactose
monohydrate (Tablettose 80 and Granulac 200) and two different types of dry mixing processes
(high-shear mixing and “in bulk” mixing) were employed. To evaluate the influence of the
variables (mixing speed, mixing time, filling level of the high-shear and cube mixer, lactose
monohydrate type) and their interactions upon the response (content uniformity of Alprazolam in
the powder blends), a Factorial 24 design (with 4 factors at 2 levels in 1 block) was generated for
each type of mixer. For high-shear dry mixing the Response Surface, D-optimal Factorial 24
design (with 2 replications and 31 experiments) was used, while for the “in bulk” dry mixing the
Response Surface, Central Composite Factorial 24 design (with 34 experiments) was used. The
process parameters for the high-shear mixer were varied within the following ranges: filling level
of 70-100%, impeller mixing speed of 50-300 rpm and mixing time of 2-10 minutes. For the cube
mixer the following process parameter ranges were employed: filling level of 30-60%, mixing speed of 20-390 rpm and mixing time of 2-10 minutes. Raman spectroscopy in conjunction with
a validated Partial Least Square (PLS) regression model was used as a Process Analytical
Technology (PAT) tool for Alprazolam content determination and content uniformity monitoring.
The DoE model was further employed to optimize the powder blending process in regard to the
achievement of appropriate Alprazolam content uniformity using high-shear mixing and
Tabletosse 80 as filler. The desirability function revealed that the following process parameters:
a mixing time of 2 minutes, a mixing speed of 300 rpm and a 70% filling level of the mixer would
produce powder blends with the lowest variability in Alprazolam content. The three independent
lab batches of low-dose Alprazolam tablets, produced with high-shear mixing using these process
parameters, conformed to the requirements of the European Pharmacopoeia for content (assay) of
Alprazolam and uniformity of the dosage units

Item Type:	Article
Subjects:	Engineering and Technology > Other engineering and technologies Medical and Health Sciences > Other medical sciences
Divisions:	Faculty of Medical Science
Depositing User:	Liljana Makraduli
Date Deposited:	28 Mar 2024 12:39
Last Modified:	28 Mar 2024 12:39
URI:	https://eprints.ugd.edu.mk/id/eprint/33903

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