Need of polymers for solubility enhancement

Solubility remains a critical obstacle for pharmaceutical industry in formulation and development of new drugs. Solubility in proportion affects the bioavailability and so safety and efficacy of a drug product. In order to break this chain, solubility enhancement raises as the priority before any formulation. Various commercially available polymeric products are playing magnificent role in solubility aspects.

Prathamesh Bhide Pharmaceutical & Clinical Consultants, Mumbai

Amrit Karmarkar Pharmaceutical & Clinical Consultants, Mumbai

Introduction

It is an analytical composition of a saturated solution expressed as a proportion of a designated solute in a designated solvent, as defined by IUPAC. But more precisely, solubility can be described as, a ‘chemical property referring to the ability of the given substance (solute) to dissolve in a solvent’, a simple and well known quantitative terminology of science. It ranges widely from infinitely soluble or fully miscible to poorly soluble. For poorly soluble or very poorly soluble compounds, insoluble term is often applied. In the pharma industry as estimated, approximately 40 per cent of all the drugs, which are currently in the market and 90 per cent of compounds in drug delivery pipelines, are poorly water soluble. Thus low aqueous solubility create problem in reproducible absorption from gastrointestinal track, ultimately affecting the bioavailability, as well as safety and efficacy of product.

As per FDA, a drug is considered highly soluble when the highest dose strength is soluble in 250 ml or lesser amount water over a pH range of 1 to 7.5. (Volume of 250 ml is estimated from a BE protocol, that prescribe a fasting human volunteer administration of drug, with glass of water). Depending upon the solubility, drugs are classified in Biopharmaceutics Classification System (BCS).

Biopharmaceutics classification system (BCS)

It is a system used for the classification of drug substances depending upon their aqueous solubility and intestinal permeability. The main purpose of this is to increase the efficiency of drug development process. As per this system, drug substances are classified into four classes

Considerably large amount of drugs (approximately 70 per cent) fall into class II, and according to BCS, bioavailability for this class may be enhanced by increasing the solubility as drug release from dosage form and dissolution rate in GI track are the only rate limiting steps. Other class of drugs i.e. I, III and IV occupy five per cent, five per cent and 20 per cent approximately.

Need for solubility enhancement

As stated in the beginning, almost 90 per cent of the drugs are poorly soluble, creating problem in all aspects of formulation, administration, efficacy and so the financial calculations. Cost effective manufacturing without any market issues, maintaining the image and standard, is the main objective for any industry. So thinking about this aspect, the pharma industry always tries to overcome all the issues regarding quality and efficacy of products. Lower bioavailability due to poor solubility, lead to decrease in efficacy of a drug product along with patient-to-patient variability (both inter and intra) and side effects. Hence, research strategy to overcome solubility issues play a key aspect in drug development process, so as more compounds can be translated into medicines, along with improvement in efficacy, safety and reduction in cost. Need for solubility enhancement is more in case of solid dosage forms like tablets and capsules, as oral route is most convenient and commonly employed route of drug delivery.

Techniques for solubility enhancement

So what can we do to enhance solubility? Various solubility enhancing techniques can be used. These techniques can be categorised in physical, chemical and miscellaneous modifications in drug formulations. Physical modification consists of reduction in particle size, modification of crystal habit, drug dispersion like solid dispersion. Chemical modification encompasses pH change, use of buffer, derivatisation techniques etc. Miscellaneous techniques include use of adjuvant like surfactant, solbiliser, excipients, polymers etc. A popular approach to overcome solubility issues is use of polymers as solubilising excipients.

Use of technologies for solubility enhancement

Advanced technologies, innovated for the purpose of bioavailability enhancement in drug products, include some of the following:

• Spray – Dried Dispersion (SDD)
• Hot – Melt Extrusion (HME)
• Solid NanoCrystalline Dispersion (SNCD)
• Spray-Dried NanoAdsorbate Technology (SDNAD)

These technologies make use of various solubilising excipients, polymers etc resulting in increase in solubility of poorly soluble drugs. Amongst the technologies mentioned, spray-dried dispersion (SDD) and HME are the most common technologies used for solubilisation using cellulosic polymers.

Use of polymers for enhancement of solubility

Amongst the various different troubleshooting options in modifying formulations, we will focus on polymers. Polymers are the substances which consist of a large number of repeating units of monomers and whose molecules have high molar masses. These are both naturally occurring as well as synthetic. Polymers like protein, starch cellulose etc are some examples of naturally occurring polymers while plastic, resins etc belongs to synthetic polymers. In synthetic polymers, only one monomer is used but in some, two or three different monomers may be combined.

Effective solubilising polymers incline to be amphiphilic in nature, i.e. they have both hydrophobic and hydrophilic sites that helps them to interact favourably with low-solubility (i.e., hydrophobic) compounds and disperse and dissolve in aqueous environments such as the gastrointestinal (GI) tract. Interaction of polymer like self interaction, with API, with aqueous medium results in solubilising structures like micelles, colloids and ionic complexes. Solubilising polymers are used in formulations depending upon the route of administration, properties of API and formulation type.

Polymers used in formulation and drug development

Ethylcellulose, cellulose acetate phthalate (CAP), acrylate polymers, hydroxypropyl methylcellulose phthalate, polyvinyl acetate phthalate (PVAP) are some of the polymers used as solubilising excipients in formulation. These polymers, commercially, are being manufactured by industries like DOW, FMC Biopolymer, BASF, Evonik etc., under trade names like Solutol HS, Soluplus, Aquacoat, Ethocel, Eudragit and many more. These products containing different polymers are used in a variety of ways to achieve the final purpose i.e. solubility enhancement. For example, Aquacoat by FMC biopolymers (ref: www.fmcbiopolymers.com) is of three different types: Aquacoat ECD, Aquacoat ARC and Aquacoat CPD; used for sustained release coating, alcohol resistant coating and enteric coating respectively.

Some key polymers for solubility enhancement

As stated above, a variety of products consists of polymers, which are commercially developed and manufactured by a number of industries as solubility enhancement solution. These polymers differ in structure, properties, appearance. Some examples of commercially available products, their role in solubility enhancement, are as follows:

Soluplus (BASF): Soluplus is polyvinyl carpolactam-polyvinyl acetate-polyethylene glycol graft co-polymer. Soluplus have many applications but is generally used as a binder in wet granulation or dry binder in direct compression for weak soluble drugs, thus increasing its solubilisation capacity in a simple process.

Kolliphore TPGS (BASF): Kolliphore TPGS (d-a-tocopheryl polyethylene glycol 1000 succinate) is a D-alpha vitamin E ester derived from vitamin E. Kolliphore TPGS, is used for increasing solubility in tablets and capsules, by hot-melt granulation technique using TPGS as binder.

Eudragit (Evonik): It is basically used for BCS class II, III and IV drugs. Eudragit helps in enhancing solubility by using it as a carrier; drug can be dispersed into polymer as crystal or amorphous particle. Due to decrease in particle size to molecular level, solid solution provides greater effectiveness for solubility increase.

Like some of these examples, there are a number of products derived from polymers and are used in formulation, development process with necessary safety data provided for the usage of these products. In short, it can be said that, polymers have made the way easy through obstacle of solubility and hence improving efficacy, bioavailability of products, playing a big helping hand for the industries.

Conclusion

Research and development has contributed to the pharma industry upto a much greater extent with new innovation and strategies. These innovations have played a big role in overcoming various issues like poor solubility. Polymers, polymer derived products are contributing these formulations to a much greater extent, improving efficacy along with cost-effectiveness. Various different advanced technologies, applications using polymers, excipients also have also resulted in improvement of properties of drugs and resulting final quality of products. New R&D strategies and technologies will still be developed as an evolution or replacement to existing ones in near future. This chain will continue but at last it will prove beneficial for the growth of the industry.