International Journal of Pharmaceutics 206 (2000) 55–61
Robustness testing, using experimental design, of a
flow-through dissolution method for a product where the
actives have markedly differing solubility properties
M.S. Bloomfield *, W.C. Butler
Pharmaceutical De6elopment Sciences, GlaxoWellcome, Temple Hill, Dartford, Kent DA
15
AH, UK
Received 9 November 1999; received in revised form 3 July 2000; accepted 4 July 2000
Abstract
The use of experimental design for the robustness testing of a flow-through dissolution method (Ph Eur/USP
Apparatus 4) for atovaquone, one of the drug substances in a dual-active anti-malarial tablet formulation, Malarone
tablets, is described. This procedure was developed to overcome the suppression of the atovaquone solubility, caused
by the presence of the co-drug proguanil hydrochloride and potential imprecision due to the poor solubility of the
coating material in the basic dissolution media employed. For this testing a quarter fractional two-level factorial
design was applied, assessing six factors in sixteen experiments, with a further six centre points to assess natural
experimental variation. Results demonstrate that the method is robust to small changes in all the main factors
evaluated at sample times of 30 min or greater. At 15 min, variations in the concentration of sodium hydroxide in
the dissolution media, peristaltic pump speed and flow rate were assessed as statistically significant. This observation
is a result of the initial steepness of the dissolution release curve and hence these factors are now controlled routinely
in the method. Release of this poorly soluble drug is limited at the 45 min time point (Q = 75%) according to
pharmacopoeial guidelines. The approach may be applied for other dissolution procedures. © 2000 Elsevier Science
B.V. All rights reserved.
Keywords
:
Flow-through dissolution; Malarone; Experimental design; Factorial design Atovaquone; Proguanil hydrochloride
www.elsevier.com/locate/ijpharm
1. Introduction
GlaxoWellcome’s Malarone
1
tablets are regis-
tered and approved for the treatment of Plasmod-
ium falciparum malaria. The tablets contain the
actives atovaquone and proguanil hydrochloride,
and are available in two strengths containing 250
mg atovaquone and 100 mg proguanil hydrochlo-
ride or 62.5 and 25 mg of each drug, respectively.
The higher strength tablet is manufactured for
adult and the lower strength tablet for paediatric
use. Dissolution testing for the active ingredients
is routinely applied as a control on the rates of
drug release. Proguanil hydrochloride is assessed
* Corresponding author. Present address: SmithKline
Beecham R&D, St George’s Avenue, Weybridge, Surrey KT13
0DE, UK.
1
Malarone is a trademark of the GlaxoWellcome group of
companies.
0378-5173/00/$ - see front matter © 2000 Elsevier Science B.V. All rights reserved.
PII: S0378-5173(00)00509-3