QUALITY BY DESIGN-BASED FORMULATION AND OPTIMIZATION OF ARTEMETHER - LUMEFANTRINE FIXED DOSE COMBINATION I: GRANULATES ASSESSMENT
Abstract
This study was carried out to assess granulates of Artemether - Lumefantrine
(AL) fixed dose combination so as to throw more light on the effects of
processing techniques, usefulness of formulations and process method as
envisaged from adoption of principles of quality by design (QbD). Wet
granulation method was adopted; both formulation and process optimization
were done and achieved within design space (DS); and the resultant granules
were characterized for micromeritic properties and optimized to give quality
granulates that were useable in next processing stage. Characterization indices of
flow rate, angle of repose, bulk and tap densities, Hausner ratio and Carr’s index
were used to establish the bulk properties of the granulates. Evaluation of
potential risks to predefined parameters and critical quality attributes (CQAs)
was done and documented. Indications from observed quality indices elucidated
the critical nature of order of addition of AL during processing. Intrinsic potential
risks were controlled to the extent that fairly good granulates were produced with
flow rate of ≥ 0.45 g/s, angle of repose of ≤ 37.67º, bulk density of ≥ 0.48 g/ml,
tapped density of ≥ 0.54 g/ml, Hausner ratio of ≤ 1.265 and Carr’s index of ≥
11.68%. Stability study confirmed no substantial changes in the granules that
could cause instability in future when stored for 60 days at intermediate storage
conditions of 30 ±2ºC temperature and 65 ±5% relative humidity. It is considered
that the process and mode of incorporation of AL into formulations F-4 and F-6
during wet massing were capable of consistent performance as illustrated by the
achieved quality parameters of the granules.
Keywords: Characterization, index, risk, parameter, granulation, density
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