Enhancement of the Aqueous Solubility and Permeability of Poorly Water- Soluble Drugs

Nishikant A Raut ,  Assistant Professor, Department of Pharmaceutical Sciences, Rashtrasant Tukadoji Maharaj Nagpur University

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.

Introduction:

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).  

Polymorphism

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).

Cocrystals

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).

Cosolvents

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.

Surfactants

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

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).

Solid Dispersion

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.

Conclusion

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

References:

Arora KK, Zaworotko MJ. Pharmaceutical co-crystals: a new opportunity in pharmaceutical science for a long-known but little-studied class of compounds, in Polymorphism in Pharmaceutical Solids (Brittain HG ed) 2009;282–317, Informa Healthcare, New York.

Bajaj M, Monica R, P. Rao P,  Pardeshi A, Sali D, Nanocrystallization by Evaporative Antisolvent Technique for Solubility and Bioavailability Enhancement of Telmisartan, AAPS PharmSciTech 2012:13 (4);1331-1340.

Banerjee R, Bhatt PM, Ravindra NV, Desiraju GR. Saccharin salts of active pharmaceutical ingredients, their crystal structures, and increased water solubilities. Cryst Growth Des 2005; 5(6):2299–2309.

Bergström CS, Wassvik CM, Johansson K, Hubatsch I. Poorly soluble marketed drugs display solvation limited solubility. J Med Chem 2007;50(23):5858–5862.

Blagden N, de Matas M, Gavan PT, York P. Crystal engineering of active pharmaceutical ingredients to improve solubility and dissolution rates. Adv Drug Deliv Rev 2007;59(7):617–630.

Challa R, Ahuja A, Ali J, Khar RK. Cyclodextrins in drug delivery: An updated review. AAPS PharmSciTech 2005;6(2):E329-E357.

Corrigan OI. Salt forms: pharmaceutical aspects, in Encyclopedia of Pharmaceutical
Technology (Swarbrick J ed) 2007:3177–3188, Informa Healthcare, New York.

Desiraju GR. Crystal engineering: A brief overview. J Chem Sci 2010;122(5):667–675.

Di L, Kerns EH, Carter GT. Drug-like property concepts in pharmaceutical design. Curr Pharm Des 2009;15(19):2184–2194.

Giri, T.K., Alexander, A., Tripathi, D.K. Physicochemical classification and formulation development of solid dispersion of poorly water-soluble drugs: an updated review. Int. J. Pharm. Biol. Arch. 2010:1; 309–324.

Kawakami K. Modification of physicochemical characteristics of active pharmaceutical ingredients and application of supersaturatable dosage forms for improving the bioavailability of poorly absorbed drugs. Adv Drug Deliver Rev 2012;64(6):480–495.

Kerc J, Srcic S, Kofler B. Alternative solvent-free preparation methods for felodipine surface solid dispersions. Drug Dev Ind Pharm 1998;24(4):359–363.

Kipp JE. Solubilizing systems for parenteral formulation development -small molecules, in Solvent Systems and their Selection in Pharmaceutics and Biopharmaceutics (Augustijns P and Brewster M eds) 2007:309–336, Springer, New York.

Law D, Schmitt EA, Marsh KC, Everitt EA, Wang WL, Fort JJ, Krill SL, Qiu YH. Ritonavir-PEG 8000 amorphous solid dispersions: in vitro and in vivo evaluations. J Pharm Sci 2004; 93(3):563–570.

Loftsson T, Stefansson E. Effect of cyclodextrins on topical drug delivery to the eye. Drug Dev Ind Pharm 1997;23(5):473-481

Luo Y, Chen DW, Ren LX, Zhao XL, Qin J. Solid lipid nanoparticles for enhancing vinpocetine’s oral bioavailability. J Control Release 2006;114(1):53–59.

Malmsten M. Surfactants and Polymers in Drug Delivery, Marcel Dekker, New York. 2002.

Mellaerts R, Aerts C, Van JH, Augustijns P, den Mooter G Van, Martens J. Enhanced release of itraconazole from ordered mesoporous SBA-15 silica materials. Chem Commun 2007;13:1375–1377.

Merisko-Liversidge E, Liversidge GG. Nanosizing for oral and parenteral drug delivery: A perspective on formulating poorly-water-soluble compounds using wet media milling technology. Adv Drug Deliver Rev 2011;63(6):427–440.

Monkhouse DC, Lach JL. Use of adsorbents in the enhancement of drug dissolution I. J Pharm Sci 1972;61(9):1430–1435.

Newman A, Knipp G, Zografi G. Assessing the performance of amorphous solid dispersions. J Pharm Sci 2012;101(4):1355–1377.

Reddy LH, Sharma RK, Chuttani K, Mishra AK, Murthy RSR. Influence of administration route on tumor uptake and biodistribution of etoposide loaded solid lipid nanoparticles in Dalton’s lymphoma tumor-bearing mice. J Control Release 2005;105:185-198.

Rubino JT, Yalkowsky SH. Cosolvency and cosolvent polarity. Pharm Res. 1987 Jun;4(3):220-30.

Schwarz C, Mehnert W. Solid lipid nanoparticles (SLN) for controlled drug delivery. II. Drug incorporation and physicochemical characterization. J Microencapsul 1999;16(2):205–213.

Serajuddin ATM. Salt formation to improve drug solubility. Adv Drug Deliver Rev 2007;59(7):603–616.

Van Speybroeck M, Mols R, Mellaerts R, Thi T Do, Martens J, Humbeeck J Van, et al. Combined use of ordered mesoporous silica and precipitation inhibitors for improved oral absorption of the poorly soluble weak base itraconazole. Eur J Pharm Biopharm 2010;75(3):354–365.

Zhang X, Sun F, Zhang T, Jia J, Su H, Wang C, et al. Three pharmaceuticals cocrystals of adefovir: Syntheses, structures and dissolution study. J Mol Struct 2015;1100:395–400.

Nishikant A Raut

Nishikant A Raut is an Assistant Professor (Sl. Gr.) in the Department of Pharmaceutical Sciences, Rashtrasant Tukadoji Maharaj Nagpur University, Nagpur, India. He received Ph.D. Degree in Pharmaceutical Sciences from Rashtrasant Tukadoji Maharaj Nagpur University, Nagpur in 2010. He pursued Post-Doctoral Research from College of Pharmacy, University of Illinois at Chicago, USA under the prestigious Raman Post-Doctoral Fellowship awarded by University Grants Commission, He is having15 Years of Experience in the field of Pharmaceutical Sciences and his area of expertise includes Pharmaceutical analysis, solubility enhancement of Pharmaceuticals, Natural Products, Medicinal Plants and Phyto-pharmaceuticals. He has good number of publications in National and International journals to his credit. He has received research grants from DBT, SERB-DST and UGC, Govt. of India with total outlay near to 1 Cr.

TOP