Dry Blending Process Scale-Up For A Very Low Dose Drug Candidate

AAPS PharmSciTech , 2000; 1 (3) article 26 (http://www.pharmscitech.com/)

Dry Blending Process Scale-up for a Very Low Dose Drug Candidate
Submitted: May 10, 2000; Accepted: August 28, 2000

Lei-Shu Wu*, Josephine Pang, Jian-Ge Chen, and Munir A. Hussain
DuPont Pharmaceuticals Company, Wilmington, DE

INTRODUCTION DMP 543 is a pharmacologically
potent compound intended for the potentialtreatment of Alzheimer’s disease. DMP 543, 10,10-bis(2-fluoro-4pyridinylmethyl)-9(10H)-anthracenone, is poorly water soluble (2.6 µ g/mL at ~22° C) and is soluble in methanol and ethanol. DMP 543 contains no ionizable moiety in the pH range of 2-9.2 and exhibits a melting peak at 171° C by differential scanning calorimetric analysis. The drug is unstable in acidic solution. An extremely lowstrength (0.025-mg capsule with 0.02% drug load in the formulation) was used in clinical studies. Because of the low dose, content uniformity is a major concern in the process development. Proper blending and prevention of segregation, especially when wet granulation is not feasible and powder is cohesive, are required for a successful processing. Particle size distribution, particle shape, surfacecharge, and cohesiveness of materials have an impact on the mobility of particles and surface adherence to a carrier excipient. The use of a carrier that forms a structured powder with the micronized drug substance adhering on the carrier’s surface is critical for a successful formulation and process for a low-dose drug [1]. Electrostatic attraction occurs with particles having a diameter no largerthan 2 µ m, and Van der Waal forces play a role between particles with a diameter less than 50 µ m [2,3]. In addition to the drug substance, the current formulation includes lactose monohydrate (a diluent), sodium starch glycolate (a disintegrant), and magnesium stearate (a lubricant). Because of stability reasons, a wet granulation process for this potent compound was not an option unlessstabilizing agents were added. Therefore, a dry blending process was pursued. In this report, the optimized scaled-up blending process and product evaluation results are presented.

EXPERIMENTAL
MATERIALS
Micronized DMP 543 drug substance was manufactured by DuPont Pharmaceuticals at the Deep Water facility in New Jersey. The excipients included lactose monohydrate (Spray Dried 316, Foremost FarmsUSA, Rothschild, WI), sodium starch glycolate (Explotab® , Penwest Pharmaceuticals, Patterson, NY), magnesium stearate ( Mallinckrodt, Cheaterfield, MO), and white opaque #2 and #3 capsules (Capsugel, Greenwood, SC). Milli-Q water (Millipore Corp, Milford, MA) was used for preparing the dissolution medium and the high-performance liquid chromatography (HPLC) mobile phase. HPLC-grade acetonitrile,reagent-grade phosphoric acid 85%, and reagent-grade sodium phosphate, monobasic, monohydrate (all from EM, Gibbstown, NJ) were used in the preparation of the mobile phase for HPLC analysis. Whatman 0.45 µ m PVDF (Hydrophilic Polyvinylidine Fluoride membrane) filters (Whatman Science, Ann Arbor, MI) were used for sample filtration.

EQUIPMENT
The following tools and equipment were used during thedevelopmental stage: glass mortar and pestle, Patterson-Kelly Blend Master 8-qt V-Blender, Patterson-Kelly 1-cu-ft and 2-cu-ft V-Blenders (Patterson-Kelley, East Stroudsburg, PA), Gallay Blender 113L (Gallay Containers & Systems LTD, Birmingham, UK), Turbula Shaker/Mixer Model T2C *)Corresponding Author: Lei-Shu Wu, PhD. , Experimental Station, E400/1241, P.O. Box 80400 , Wilmington, DE,198800400; e-mail: lei-shu.wu@dupontpharma.com

KEYWORDS Dry Blending Process, Low Strength,
Process Scale-up, Carrier

(Willy A. Bachofen AG, Maschinenfabrik, Germany), Zanasi ZA5 Capsule Filler (Nuova Zanasi IMA Group, Ozzano Emilia, Italy), Bosch 400 Ccapsule Filler (Bosch, Waiblingen, Germany), Se-Jong SF-30 Capsule Filler (Se-Jong Machinaery Co LTD, Kyoungki-Do, Korea), and JEOL JSM 840...