Formulation design for poorly water-soluble drugs based on biopharmaceutics classification system: Basic approaches and practical applications
ABSTRACT The poor oral bioavailability arising from poor aqueous solubility should make drug research and development more difficult. Various approaches have been developed with a focus on enhancement of the solubility, dissolution rate, and oral bioavailability of poorly water-soluble drugs. To complete development works within a limited amount of time, the establishment of a suitable formulation strategy should be a key consideration for the pharmaceutical development of poorly water-soluble drugs. In this article, viable formulation options are reviewed on the basis of the biopharmaceutics classification system of drug substances. The article describes the basic approaches for poorly water-soluble drugs, such as crystal modification, micronization, amorphization, self-emulsification, cyclodextrin complexation, and pH modification. Literature-based examples of the formulation options for poorly water-soluble compounds and their practical application to marketed products are also provided. Classification of drug candidates based on their biopharmaceutical properties can provide an indication of the difficulty of drug development works. A better understanding of the physicochemical and biopharmaceutical properties of drug substances and the limitations of each delivery option should lead to efficient formulation development for poorly water-soluble drugs.
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- "This is by far the most challenging case for the drug development as well as their formulation design. It is widely accepted, however, that formulation approaches similar to those for BCS class II drugs (improvement of the solubility and the dissolution behavior) could be practically applied to BCS class IV drugs, even though the absorption could be limited by the poor permeability after dissolving (Kawabata et al., 2011). One of the common procedures to improve the aqueous solubility of a drug is salt formation using a suitable counter ion. "
ABSTRACT: New salts of antibiotic drug ciprofloxacin (CIP) with pharmaceutically acceptable maleic (Mlt), fumaric (Fum) and adipic (Adp) acids were obtained and their crystal structures were determined. The crystal lattices of the fumarate and adipate salts were found to accommodate the water molecules, while the maleate salt was anhydrous. The dehydration and melting processes were analyzed by means of differential scanning calorimetry and thermogravimetric analysis. Solubility and intrinsic dissolution rates of the salts were measured in pharmaceutically relevant buffer solutions with pH 1.2 and pH 6.8. Under acidic conditions, the salts were found to be less soluble than the parent form of drug, while the [CIP+Fum+H2O] and [CIP+Mlt] solids showed enhanced dissolution rate when compared to a commercially available ciprofloxacin hydrochloride hydrate. In the pH 6.8 solution, all the salts demonstrated solubility improvement and faster dissolution rate with respect to pure CIP. Copyright © 2015. Published by Elsevier B.V.European journal of pharmaceutical sciences: official journal of the European Federation for Pharmaceutical Sciences 06/2015; 77. DOI:10.1016/j.ejps.2015.06.004 · 3.01 Impact Factor
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- "Compared with matrix materials such as Solutol 1 HS 15, Cremophor 1 RH 40 and Tween 1 80 (Strickley, 2004), Soluplus 1 can serve either as a solubilizer to form micellar structures in the aqueous medium or as a matrix material for solid dispersions. Moreover, Soluplus 1 based solid dispersions were demonstrated to significantly improve the solubility or oral bioavailability of poorly water-soluble drugs (Kawabata et al., 2011). "
ABSTRACT: Our study aimed to develop an amorphous 9-nitrocamptothecin solid dispersion (9-NC-SD) using polyvinyl caprolactam–polyvinyl acetate–polyethylene glycol graft copolymer (Soluplus®) for improving its oral bioavailability and antitumor efficacy in vivo. Freeze-dried 9-NC-SD with an optimized drug/polymer ratio at 1:15 (w/w) was characterized by powder X-ray diffraction, scanning electron microscopy and Fourier transform infrared spectroscopy. The amorphous form of 9-NC was obtained by freeze-drying and the aqueous solubility of 9-NC was increased to 1.42 mg/mL. Upon dilution, 9-NC-SD was proven to form micellar structures with an average size distribution around 58 nm ± 5 nm (PDI = 0.107 ± 0.016). Moreover, 9-NC-SD showed significantly increased intracellular uptake efficiency in Caco-2 cells compared to free 9-NC. Furthermore, the AUC0–8 h of 9-NC-SD following oral administration showed a 2.68-fold increase in the lactone form of 9-NC compared to that of free 9-NC in Sprague-Dawley rats. The 9-NC-SD did not show obvious inflammatory responses and gastrointestinal toxicity following oral administration as demonstrated by the histological analysis of the rat intestinal sections. Thus, 9-NC-SD represents a promising approach for improving the solubility and oral bioavailability of drugs with poor solubility.International Journal of Pharmaceutics 12/2014; 477(1). DOI:10.1016/j.ijpharm.2014.10.055 · 3.79 Impact Factor
- "Solid dispersion is one of the approaches to increase the dissolution rate of poorly water soluble drugs. Solid dispersion may be defined as dispersion of active ingredientswithinan inert carrier in solid state (Bhowmiket al., 2012; Leuner and Dressman, 2000; Kawabataet al.,2011; Chenet al.,2011). Solubility of LOV was increased by using solid dispersion techniques (Patel et al., 2008; Shaikh et al, 2011). "