Formulation design for poorly water-soluble drugs based on biopharmaceutics classification system: Basic approaches and practical applications

Department of Pharmacokinetics and Pharmacodynamics and Global Center of Excellence (COE) Program, School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Suruga-ku, Shizuoka 422-8526, Japan.
International Journal of Pharmaceutics (Impact Factor: 3.65). 08/2011; 420(1):1-10. DOI: 10.1016/j.ijpharm.2011.08.032
Source: PubMed

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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    • "Methods that are available to eliminate the solubility problem (Fahr and Liu, 2007; Sarode et al., 2014) are either costly or their industrial applicability is limited. The dissolution rate of APIs belonging to, the BCS II group can effectively be improved by use of salt forms with enhanced dissolution profiles (Agharkar et al., 1976), by solubilisation of drugs in co-solvents (Amin et al., 2004), by micellar solutions (Torchilin, 2007), by formation of water-soluble complexes (Casella et al.,1998), by use of lipidic systems for the delivery of lipophilic drugs (Humberstone and Charman, 1997), by increasing the specific surface area of the API according to the Noyes–Whitney equation (Kawabata et al., 2011; Whitney and Noyes, 1897) or by forming solid dispersions of amorphous APIs (Sekiguchi et al.,1964; Simonelli et al., 1969; Van Drooge et al., 2006). The combinations of the last two mentioned methods can be achieved by solvent based technologies, such as spray drying (SD) and electrospinning (ES). "
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    ABSTRACT: Three solvent based methods: spray drying (SD), electrospinning (ES) and air-assisted electrospinning (electroblowing; EB) were used to prepare solid dispersions of itraconazole and Eudragit E. Samples with the same API/polymer ratios were prepared in order to make the three technologies comparable. The structure and morphology of solid dispersions were identified by scanning electron microscopy and solid phase analytical methods such as, X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC) and Raman chemical mapping. Moreover, the residual organic solvents of the solid products were determined by static headspace-gas chromatography/mass spectroscopy measurements and the wettability of samples was characterized by contact angle measurement. The pharmaceutical performance of the three dispersion type, evaluated by dissolution tests, proved to be very similar. According to XRPD and DSC analyses, made after the production, all the solid dispersions were free of any API crystal clusters but about 10 wt% drug crystallinity was observed after three months of storage in the case of the SD samples in contrast to the samples produced by ES and EB in which the polymer matrix preserved the API in amorphous state. Copyright © 2015. Published by Elsevier B.V.
    International Journal of Pharmaceutics 08/2015; 494(1). DOI:10.1016/j.ijpharm.2015.07.076 · 3.65 Impact Factor
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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. "
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    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 · 3.35 Impact Factor
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    • "The poorly water soluble drug indicate low absorption and bioavailability is often controlled by the rate of dissolution of the drug in the gastrointestinal tract. Many approach has been done for enhancing the dissolution characteristics of slightly water-soluble drugs included reduce particle size, crystal modification, cyclodextrin complexation and self-emulsification (Kawabata et al., 2011). Solid dispersion also has been reported to increase dissolution of disulfiram and indomethacin (Ramadhani et al., 2014; Sunil et al., 2012). "
    04/2015; 26(2):71. DOI:10.14499/indonesianjpharm26iss2pp71
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