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Rapid advances in drug discovery have led to the identification of a number of compounds with good therapeutic potential.
However, because of their complex chemistry, the majority of these compounds have poor aqueous solubility resulting in reduced
and variable bioavailability.1–3 Current marketed formulations of sparingly water-soluble drugs such as Ketoconazole (KC), a imidazole antifungal agent used
for treatment of fungal infections,4 Fenofibrate (FF), a fibric acid derivative used for the treatment of hypertriglyceridimia,5 and Candesartan cilexetil (CC) a non-peptide angiotensin II type 1 receptor antagonist used in the treatment of hypertension,
are suboptimal.6 Following oral administration, absorption of these drugs from the gastrointestinal (GI) tract is dependent on their solubility
in Gl fluids. Poorly soluble drugs generally have low dissolution velocity and exhibit a small concentration gradient across
the intestinal mucosa, which can result in low, variable absorption and a poor therapeutic response.
Based on the understanding that the rate of drug dissolution is the primary driving force behind improved pharmacokinetic
properties, these drugs were formulated as nanometer-sized particles — particles <1 μm. The increase in surface area because
of the reduction in particle size can substantially increase dissolution rate if the formulation disperses into discrete particles.7
Nanocrystalline dispersion comprises drug, water and stabilizers. Stabilizers used to aid the dispersion of particles are
either polymers and/or surfactants. Polymers act as the primary stabilizer whereas surfactants are used as the secondary stabilizer.
To be effective, the stabilizers must wet the drug crystals and provide a steric and ionic barrier to prevent agglomeration.
The concentration of polymeric stabilizers can range 1–10% w/v and the concentration of surfactants is generally <2% w/v.8 If required, other excipients, such as buffers, salts and diluents, such as sugar, can be added to enhance physical stability
and further processing.
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The bead milling process used for the production of drug nanoparticles can be described as a simple procedure comprising attrition
media, suspension and agitation. The extent of size reduction is governed by the grinding energy, which is determined by the
intrinsic hardness of the drug, grinding media and milling power. The nanoparticulate dispersion was converted into solid
intermediates for tabletting by granulating with water-soluble carriers. The dissolution characteristics of tablet formulations
containing drug nanoparticles were compared with commercial formulations in physiologically relevant dissolution media.
Materials and methods
Materials. FF, KC and CC were procured from Dr. Reddy's Laboratories (India). Lactose monohydrate was purchased from Roquette Frères
(France). Hydroxypropyl methylcellulose (HPMC, 6cps) was purchased from Colorcon (India). Sodium lauryl sulphate was purchased
from Qualigen Fine Chemicals (India). Crospovidone (Polyplasdone) and sodium starch glycolate were obtained from International
Specialty Products (Wayne, NJ, USA [ISP]) (USP) and Grain Processing Corp. (Muscatine, IA, USA), respectively. All other chemicals
were of analytical reagent grade.
Preparation of nanosuspension on a laboratory scale. A glass apparatus mimicking the media milling machine was fabricated in-house for identifying the appropriate stabilizer,
along with its concentration, for the preparation of nanoparticulate dispersions with adequate physical stability and the
production of solid intermediates required for solid dosage form processing.9
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