Geetanjali Laghate and Dr Heeshma Shah, Technical Services Department, Signet Chemical Corporation, Mumbai, give an insight of various excipients and strategies that can be used for solubility enhancement by using different techniques
The pharmaceutical industry is facing enormous challenges in formulating poorly soluble active pharmaceutical ingredients (APIs) including new chemical entities (NCE) which are approved and under development. These molecules possess poor physicochemical properties like low aqueous solubility and low permeability both of which lead to poor bioavailability [1,2]. Scientists are therefore focusing on developing formulation strategies for increasing the therapeutic effectiveness of these molecules via an appropriate selection of excipients. Various excipients and strategies that can be used for solubility enhancement by using different techniques are elaborated [3,4] .
Solvents / co-solvents
The addition of a water-miscible or partially miscible organic solvent /co-solvent, is one of the most common and effective ways to increase solubility of poorly soluble molecules which are generally weak electrolytes, highly crystalline and lipophilic in nature. Co-solvents act by decreasing the interfacial tension between aqueous solution and lipophilic solute to facilitate solubilisation. Some co-solvents extensively used in marketed formulations are propylene glycol (Kollisolv PG), low molecular weight polyethylene glycols (Kollisolv PEG 300 and 400), polyoxyl castor oil derivatives (Kolliphor EL and ELP), glycerin, medium chain triglycerides (Kollisolv MCT 70), long chain triglycerides like corn oil and olive oil, dmimethyl sulfoxide, ethanol, etc. Although a simple and quick approach, precautions need to be taken while using co-solvents to avoid precipitation of the solute on exposure to aqueous media and biological fluids.
Solubilisers: Surface active agents or surfactants are amphiphilic molecules having a polar head group and non-polar tail. The head group can be cationic, anionic or non-ionic in nature. They function by lowering the surface tension and improve the dissolution of lipophilic, poorly soluble APIs. Beyond a specific concentration known as the critical micelle concentration (CMC), the surfactant molecules self assemble to form aggregates known as micelles. Drug molecules get entrapped within these micelles which in turn increases their solubility.
The CMC for most surfactants is very low. For non-ionic
surfactants it is in the range of 10-5 mol/L. The CMC is slightly higher for ionic surfactants and micelle formation is difficult due to electrostatic repulsion between the charged polar groups and is in the range of 10-3 mol/L. Non-ionic surfactants are the ones which are mostly used for formulation development. Notable examples found in marketed formulations are polyoxly 35 castor oil (Kolliphor EL), polyoxyl 40 hydrogenated castor oil (Kolliphor RH 40), polyoxyl-15-hydroxystearate (Kolliphor HS 15), Poloxamers (Kolliphor P 188, Kolliphor P 407 , Kolliphor P 124), D-alpha-tocopherol polyethylene glycol 1000 succinate (Kolliphor TPGS), Polysorbates (Kolliphor PS 60, Kolliphor Ps 80), sorbitan mono oleate (Span 60, Span 80), etc. Apart from facilitating dissolution by micellar solubilisation, surfactants also play an important role in stabilising suspensions, formation of micromulsions and self emulsifying drug delivery systems . Microemulsions are thermodynamically stable, transparent, low viscosity, isotropic dispersions consisting of oil and water stabilised by an interfacial film of surfactant molecule in conjunction with a co-surfactant. Water soluble, water insoluble and amphiphilic drugs can be incorporated in these systems. Self emulsifying and self micoremulsifying drug delivery systems (SEDDS and SMEDDS) are isotropic solutions of oil and surfactant which form oil in water microemulsions on mild agitation in the presence of water. Poorly soluble drugs can be dissolved in the oil surfactant mixture which is known as a pre-concentrate. On oral administration they behave as microemulsion and enhance the bioavailability of the API. Examples of oils used in the formulation of microemulsions, SEDDS and SMEDDS are caprylic/capric triglycerides (Capryol), polyglycolysed glycerides (Labrafil and Labrasol), medium chain triglycerides, (Kollisolv MCT) etc. [7,8] These oils are used along with the surfactants listed above. Another way of enhancing the solubility of poorly soluble drugs is by formulation of liposomes. They are closed spherical vesicles composed of outer lipid bilayer membranes and an inner aqueous core with an overall diameter of < 100 microns. They can be produced from cholesterol, non-toxic surfactants, sphingolipids, long chain fatty acids and phospholipids like hydrogenated soya phosphatidiyl choline (HSPC), Distearoylglycero phosphoethanolamine (DSPE), Dipalmitoylglycerophosphoglycerol sodium salt (DPPG, Na), MPEG-ylated phospholipids like MPEG-DSPE [9,10].
To summarise, due to the ease of availability and relatively non-toxic nature as compared to organic co-solvents, solubilisers were and still are the most widely used excipients for solubility enhancement.
Complexation: Cyclodextrins are cyclic (a-1,4)-linked oligosaccharides of a-D-glucopyranose comprising of a hydrophobic central cavity to accommodate the drug molecule to form an inclusion complex and hydrophilic outer surface. They are classified as a, ß or ? corresponding to 6, 7 or 8 glucopyranose units. Out of these, ß-cyclodextrins (ß-CD) are widely preferred in the industry. They act by making the drug available at the surface of the biological membranes from where it partitions without interfering with the lipid bilayer thereby making the drug bioavailable. In addition to the natural cyclodextrins, two synthetic water soluble derivatives i.e. hydroxypropyl ß-cyclodextrin (HP ß-CD) and sulfobutylether- ß-cyclodextrin sodium salt have generated interest due to the advantages of greater solubility, tolerability and safety. Though ß-CD and HP ß-CD are less toxic as compared to surfactants and co-solvents, the limitation of this technique is that the drug needs to have the ability to form complexes which may not be possible in some cases. [11,12]
Solid dispersions: The stable form of a drug molecule is crystalline in nature and poses problems in solubilisation due to its high lattice energy. On the other hand, the disorderly/irregular amorphous form offers an advantage over crystalline forms with respect to solubility inspite of its poor physical and chemical stability. New techniques that render the amorphous form stable are becoming increasingly popular; can be achieved either by making the API amorphous or by formulating an amorphous delivery system. For both approaches, solid dispersion technology is used extensively. These are systems where one component is homogenously dispersed in a carrier matrix (which is usually polymeric and often amorphous) and when the whole system appears to be in a solid state. They can be formulated primarily by two methods viz. melting method and solvent evaporation by using processes like spray drying, spray congealing, spray layering and hot melt extrusion among others. Amorphous solid dispersions can be stabilised if the ‘freezing effect’ is sufficient due to a high glass transition temperature of the system or, better, by interaction such as hydrogen bonding formation between the dispersed drug and the polymeric or amorphous carrier. When exposed to the aqueous GI environment these systems produce supersaturated solutions to achieve optimum release. Commonly used matrix formers are homopolymers, copolymers, amphiphilic copolymers. These may be used in combination with solubilisers and plasticisers. Notable examples of matrix formers are polyvinyl pyrrolidone- poly vinyl acetate (Kollidon VA 64), Hypromellose acetate succinate (AQOAT), Hypromellose (Pharmacoat), povidones (Kollidon 30, Kollidon 90F), polyvinyl caprolactum-polyvinyl acetate-polyethylene glycol graft co-polymer (Soluplus), Polymethyl methacrylates. These polymers can be used alone or in combination with one or more surfactants like Poloxamers (Kolliphor P 188, Kolliphor P 407), polyethylene glycols (Kollisolv PEG 300 and 400), and Vitamin E polyethylene glycol succinate (Kolliphor TPGS). The concept of solid dispersions has been applied to many marketed formulations and has resulted in clinical benefits by increasing the bioavailability poorly soluble API [13,14,15].
Understanding the rate limiting step in oral absorption is important in the selection of appropriate excipients and designing formulation approaches which are simple and cost effective. A combination of good science and good judgment help in overcoming the challenge posed by poorly soluble drugs and meeting stringent development timelines.
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