Development and Evaluation of Lyophilized Methotrexate Nanosuspension using Quality by Design Approach.

Ashok Hajare,Trupti Powar,Sopan Nangare,Ravindra Jarag

doi:10.17344/acsi.2021.6858

Abstract

With the application of the quality by design (QbD) approach, a high-pressure homogenizer (HPH) methodology was employed to develop methotrexate nanosuspension (MTX-NS) to boost bioavailability. The Ishikawa diagram was used to analyze potential risk factors in formulation development. To screen and study the impact of various formulation and process factors on the critical quality attributes (CQA), the Placket-Burman design and central composite design were utilized. The number of HPH cycles, poloxamer 188 concentration, and tween 80 concentration were shown to be significant parameters (P<0.05), that were further optimized using Central Composite Design. The zeta potential of optimized lyophilized MTX-NS was determined to be -11.6 ± 7.52 mV and the average particle size was 260 ± 0.25 nm. In vitro cytotoxicity experiments revealed a greater than 80% inhibition, with apoptotic cells shrinking, fragmentation, and cell death. Furthermore, the Cmax and AUC0-t were increased by 2.53 and 8.83 folds, respectively. The relative bioavailability of MTX-NS was found to be 8.83 times higher than that of MTX-aqueous dispersion. As a result, the QbD method resulted in the development of a lyophilized MTX-NS with process understanding and control based on quality risk management.

Highlights

Pharmaceutical experts have long struggled with the formulation and development of poorly water-soluble drugs, and these challenges are projected to worsen since more than 40% of new chemical entities discovered by drug discovery are poorly aqueous soluble.[1]
A stable methotrexate nanosuspension (MTX-NS) system with a suitable stabilizer was optimized by various factors such as sedimentation effect, suspending effects, and particle size analysis (Table S5).[18,28]
The outcomes of this study indicated that the values of IC50 of NS are lower than MTX-aqueous dispersion (AQD) at the same incubation time (48 h)

Summary

Introduction

Pharmaceutical experts have long struggled with the formulation and development of poorly water-soluble drugs, and these challenges are projected to worsen since more than 40% of new chemical entities discovered by drug discovery are poorly aqueous soluble.[1]. Traditional approaches including solubilization by surfactant, surfactant dispersion, micronization, use of the oily solution, permeation enhancers, which evolved too earlier, that address the challenges of formulation and have limited use.[2,3] The major milestone has been achieved in the development of poorly water-soluble drugs using various newer technology, but to date, there is no universal thumb approach applicable to all active pharmaceutical ingredients.[3] a new approach has been progressively required to deal with formulation issues that are associated with the delivery of poorly soluble drugs, to enhance their therapeutic efficacy and maximize their pharmacodynamics therapy.[2]. The development of a proper dosage form is an essential element to achieve this objective.[4] From its inception, oral drug delivery is the most commonly used route of administering the drug in various dosage forms due to

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Conclusion