Bereiding van een combiantietherapietablet met artemether en amodiaquine hydrochloride d.m.v. een composiet design

Abstract

According to the recent recommendations of the WHO, an artemisinin combination therapy (ACT) tablet was developed.
Based on the literature, amodiaquine hudrochloride and artemether (an artemisinin derivative) were selected.
The dose of amodiaquine is 500mg/day and the dose of artemether is 200mg/day.
Due to these high amounts, the option was chosen for two tablets a day, each containing 250 mg amodiaquine base and 100 mg artemether.
Due to the poor flowability of the amodiaquine powder, wet granulation for the tabletting was selected.
The other excipients were used in low concentrations to reduce the size of the tablets.
The selected excipients were polyvinylpyrrolidone (PVP) as binder, Ac-Di-Sol® as disintegrant, lactose as filler and Aerosil® 200 and Mg-stearate as glidants.

In the first instance, a central composite design was used for the preparation of the ACT tablets.
Three factors were retained namely, the concentration of the binder, the concentration of the disintegrant and the compression force.
The limits of the design were fixed with pretests.
With all the design points, tablets were made and evaluated on variation of weight,
hardness, friability and disintegration time.
A polynomial equation was drawn which best describes the results. These results were evaluated by calculating the lack of fit. The results were also drawn in 3-D plots.
Although the hardness was always more than sufficient (78-200 N), friability and disintegration time together never responded to industrial requirements.
Also from the 3-D plots no region could be defined that could produce acceptable tablets.

In the second instance, another excipient was chosen. Besides PVP, starch was selected for the wet granulation step. Also these tablets were not acceptable. Capping and disintegration times of more than 20 minutes were noted.

With the partial replacement of the binder PVP by Klucel® EF, addition of Avicel® PH 102 and adaptation of the concentration of the glidants, acceptable tablets were obtained. The tablets had a hardness of 151 N, a friability of 0.38% and a disintegration time of 4 min 30 seconds. These tablets can be used for further evaluation: validation of the analysis of the two actives, chemical stability as a function of time and lastly evaluation of the bioavailability and efficacy tests.

Date of Award	2006
Original language	Dutch
Supervisor	Jacqueline Vercammen (Promotor) & Els Marchand (Co-promotor)