Drugs demonstrate a pharmacological intended role when its response is significant; which depends upon the series of events and subsequent administration. At the site of absorption, drug solubility in the biological fluid is the rate-limiting step. Most of the drugs developed these days posses a poor aqueous solubility because of high throughput screening techniques used during development. This issue poses a critical problem towards product development process and in turn for product efficacy through bioavailability. Thus, the strategies to address the problems of poor solubility during the early stage of drug discovery and development become obligatory. This article addresses various approaches for enhancement of solubility and permeability of poorly water-soluble drugs.
Combinatorial chemistry, High Throughput Screening technique (HTS) and other computeraided methods have proved their usefulness for drug design and development with requisite pharmacological activity (Bajaj et al., 2012). To attain increased potency, receptor binding is utmost important, where receptors demand highly lipophilic and poorly water-soluble drug candidates to interact with them. As a result, development of drug candidates with limited aqueous solubility (Giri et al., 2010) and dissolution rates are indispensable (Bergström et al., 2007). To overcome solubility problems during drug development, several attempts were made by the scientists. However, more than 90 per cent of the drugs approved since 1995 have either poor solubility, poor permeability, or both (Serajuddin, 2007). Di et al. (2009) reported that, around 75 per cent of compounds under development are poorly water-soluble leading to low bioavailability for approximately 16 per cent of all marketed drugs. This has triggered the setting of strategies to overcome poor aqueous solubility during the early stage of drug discovery and development. Nevertheless, this may lead to complete loss of therapeutic activity or diminished potency. In such cases, a comprehensive formulation strategy becomes imperative to support the clinical development of poorly soluble drugs for oral delivery.
Formulation approaches for improving aqueous solubility
There are several approaches for the improvement of aqueous solubility of poorly soluble drugs. Some of them are briefly discussed below.
Buffers and Salt Formation
This technique is suitably employed to improve solubility of ionisable compounds by enhancing the polarity and adjusting pH of the solution. Salt formation is the ionic interaction between weakly acidic or basic drugs with an oppositely charged counter ion causing a change in pH of the solution when salt dissolves and dissociates in water. The physicochemical properties and dissolution profile of parent drug is also altered upon isolation as salt form after salt formation. (Corrigan, 2007).
Different crystalline forms of the same compound differing in a molecular arrangement in the crystal lattice are called polymorphs and the phenomenon is called as polymorphism. These polymorphs possess different physicochemical properties such as solubility, dissolution and stability affecting oral bioavailability of poorly aqueous soluble drugs (Law et al., 2004). This crystal engineering technique is employed for generating crystal with a specific and desired characteristic (Desiraju, 2010) which may be advantageous in overcoming solubility limitations (Blagden et al., 2007).
In recent days, there is a dramatic increase in development of pharmaceutical cocrystals by academic and industrial scientists. Cocrystals are molecular species of two or more chemical entities held together by intermolecular forces of attractions. (Arora and Zaworotko, 2009). Molecular interaction between cocrystal former and a drug forms cocrystal with noncovalent or non-ionic bonding resulted in improved aqueous solubility of drug (Zhang et al., 2015). Improved solubility of the drug in turn enhances dissolution rate and permeability of drug (Banerjee et al., 2005).
In this technique, water-miscible organic solvent of low polarity is used to solubilise drug and the phenomenon is known as cosolvency (Rubino, 1987). Drug candidates without ionisable functionalities and moderate log P values are most suitable for cosolvency (Kipp, 2007). Interfacial tension between the water molecules and hydrophobic solute reduced by cosolvent system causing disruption of intermolecular hydrogen bonding networks thereby decrease the polarity of the solvent. Cosolvent system has hydrogen bond donor-acceptor groups attached to a small hydrocarbon region. The hydrophilic region ensures water miscibility, while hydrophobic region interferes with hydrogen bonding network, reducing the overall intermolecular attraction of water. Furthermore, this leads to the disruption of ability of water to self-associate and to squeeze out nonpolar, hydrophobic compounds. This reduced polarity and favourable environment with physicochemical properties more similar to poorly water-soluble drug made it solubilise in aqueous medium.
As the name suggests, surfactants are the surface active agents commonly used to solubilise poorly water-soluble drugs by improving wetting and stabilisation of formulations (Malmsten, 2002). Self-association of surfactant molecules in aqueous medium facilitates the formation of micelles. These micelles enhance the aqueous solubility of lipophilic poorly water-soluble drugs via hydrophobic micelle core and interaction with head groups with incorporation into the water-micelle interface.
Cyclodextrins (CDs) are cyclic oligosaccharides with unique molecular structure of ‘pseudo-amphiphilic’ nature. This unique molecular structure is responsible for the formation of host inclusion complexes with poorly water-soluble drugs. Several other members of this family (CDs) are widely used in pharmaceutical and allied industries. Enzymatic degradation of starch is usually done through glucosyl-transferase to generate cyclic oligomers of CDs. Several molecules can be converted into inclusion complexes only because of noncovalent interaction with lipophilic inner cavities and hydrophilic outer surfaces of CDs (Challa et al., 2005). CDs enhance bioavailability of poorly water-soluble drugs by increasing drug solubility, dissolution and permeability by making the drug available at the surface of the biological barrier (e.g., skin and mucosa) to partition into the membrane without disrupting the lipid layers (Loftsson and Stefansson, 1997).
Particle size reduction
This technique allows greater molecular interaction of solute and solvent molecules by the fact that particle size reduction greatly increases the surface area of solute resulted in enhanced solubility. The Solubility of the drug is directly proportional to the surface area of the particle; smaller the particle greater the surface. Particle size reduction is a “top-down” process, where larger particles are fragmented into smaller particles (micronisation). The methods employed for particle size reduction applies mechanical (comminution, spray drying, etc) or physical (milling, grinding, etc) stress upon the drug. Adaption of the method for size reduction depends upon the physical and chemical properties of the drug. The technologies that are able to generate nanosized drug particles resulted in significant increase in dissolution rate and apparent drug solubility. Particle size reduction technologies are routinely used to improve the oral bioavailability of poorly water-soluble drugs (Merisko-Liversidge and Liversidge, 2011).
Lipid-Based Formulations (LBF)
Dietary lipids, fat-soluble vitamins and sterols are used for lipid-based formulations. Dietary lipids and lipophilic nutrients being a component of an adult’s diet are well absorbed in the body. Thus, co-administration of drugs in lipid-based formulations is advantageous to support drug absorption. Lipids may be formulated into a range of delivery systems for oral or parenteral administration. LBF technique is relatively simple to improve aqueous for many poorly water-soluble drugs.
Drug adsorption to microporous adsorbents
In this technique, the drug is adsorbed on to the microporous adsorbents such as fumed silica dioxide (Monkhouse and Lach, 1972). This silica carrier system is also termed as “surface solid dispersions” due to their similarities with solid dispersion system; however the mechanism is completely different (Kerc et al., 1998). The enhancement of oral bioavailability of poorly water-soluble drug is facilitated by microporous adsorbents through better dissolution as compared to the unmodified crystalline material (Van Speybroeck et al., 2010). In adsorbed amorphous systems, crystallisation of drug is restricted through interaction with the carrier surface. If the carrier is porous, the narrow dimensions of the fine capillary network reduce mobility and limit crystal growth (Mellaerts et al., 2007).
Solid Lipid Nanoparticles (SLN)
This is quite older technique emerged more than 25 years ago for delivering drug with the improved oral bioavailability of poorly water-soluble drugs (Luo et al., 2006). Mostly, SLN’s are used for parenteral administration of poorly water-soluble drugs (Reddy et al., 2005), enhanced topical drug delivery, controlled drug release and targeted drug delivery. The drug-loading capacity of SLN’s for lipid soluble drugs may be high; however, low drug loading for less lipid-soluble compounds may limit its applicability (Schwarz and Mehnert, 1999).
Sekiguchi and Obi (1961) were the first to introduce Solid Dispersion (SD) to the scientific fraternity and since then it is used extensively in pharmaceuticals (Newman et al., 2012). SD is defined as a formulation in which API is dispersed in an inert matrix (Kawakami, 2012). SD is a widely explored means of enhancing dissolution and oral bioavailability of poorly water-soluble drugs. In SD formulations drug is physically dispersed within an inert and usually highly water-soluble carrier and may exist in the carrier in multiple physical forms. Depending upon the physical states of drug and carrier, SD is categorised as solid solutions, eutectic mixtures, solid amorphous dispersions, molecular dispersions, amorphous molecular dispersions, coprecipitates and sugar glasses. In SD, a drug is either molecularly mixed in solution or as a crystalline or amorphous dispersion. SD containing amorphous drug provides the most significant increase in solubility, dissolution and oral bioavailability.
Polymer stabilised nanoparticle formulations, drug-excipient complexes and formulations containing amorphous drug stabilised via adsorption to a high-surface-area solid carrier are also described as SD. In SD, drug is molecularly dispersed or suspended throughout an inert carrier and crystallisation is slowed primarily through an increase in viscosity and a decrease in drug mobility.
The methods discussed above are able to address the problem of poor aqueous solubility and permeability of drug substances. Basically, drug dissolution is a rate-limiting factor for the oral absorption of poorly water-soluble drugs from GIT. If molecular level knowledge about the drug is known then it becomes easy to choose the appropriate method for solubility enhancement. The described methods alone or in combination can be adapted to solve the solubility related issues. So, appropriate selection of solubility enhancement method is the determining factor to ensure enhanced solubility and permeability. This consequently improves oral bioavailability and reduce dosing frequency to improve patient compliance with low cost of the therapy.
Keywords: Solubility Enhancement, Permeability, Bioavailability, Drug Development
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