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


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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    • "In recent years, over 40% of the currently marketed active pharmaceutical ingredients (APIs) have been reported to have poor water solubility problems, leading to a limited and variable bioavailability of APIs [1] [2]. In order to improve the solubility and dissolution of these poorly water-soluble APIs, numerous solubility improvement approaches have been developed and commonly categorized into physical modifications, chemical modifications, and other techniques [3] [4] [5]. Solid dispersion is one of the well-known physical modification approaches to improve the dissolution rate and bioavailability of the poorly water-soluble drugs [6] [7] [8], in which the drug's particle size might be markedly reduced, molecularly dispersed or completely dissolved within the high molecular weight water-soluble polymers. "
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    Asian Journal of Pharmaceutical Sciences 10/2015; DOI:10.1016/j.ajps.2015.09.005
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    • "). The amorphization of the drugs is a preferred way in pharmaceutical sciences of enhancing the bioavailability and increasing solubility, optimizing delivery of the drug (Kaushal et al., 2004; Kawabata et al., 2011). Hence, this is another major advantage of the supercritical impregnation process. "
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    ABSTRACT: Ureteral stents are indispensable tools in urologic practice. The main complications associated with ureteral stents are dislocation, infection, pain and encrustation. Biodegradable ureteral stents are one of the most attractive designs with the potential to eliminate several complications associated with the stenting procedure. In this work we hypothesize the impregnation of ketoprofen, by CO2-impregnation in a patented biodegradable ureteral stent previously developed in our group. The biodegradable ureteral stents with each formulation: alginate-based, gellan gum-based were impregnated with ketoprofen and the impregnation conditions tested were 100bar, 2h and three different temperatures (35°C, 40°C and 50°C). The impregnation was confirmed by FTIR and DSC demonstrated the amorphization of the drug upon impregnation. The in vitro elution profile in artificial urine solution (AUS) during degradation of a biodegradable ureteral stent loaded with ketoprofen was evaluated. According to the kinetics results these systems have shown to be very promising for the release ketoprofen in the first 72h, which is the necessary time for anti-inflammatory delivery after the surgical procedure. The in vitro release studied revealed an influence of the temperature on the impregnation yield, with a higher impregnation yield at 40°C. Higher yields were also obtained for gellan gum-based stents. The non-cytotoxicity characteristic of the developed ketoprofen-eluting biodegradable ureteral stents was evaluated in L929 cell line by MTS assay which demonstrated the feasibility of this product as a medical device.
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    • "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.
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