Solubility – Meeting the challenge
Craig Grant , global director of solid form and particle engineering at Veranova , discusses the company ’ s approach to meeting solubility challenges in drug development .
In recent years , the small molecule drug discovery process has shifted towards increasingly insoluble APIs . Currently , close to 40 % of marketed drugs are classified as having low solubility under Class II and IV according to the Biopharmaceutical Classification System ( BCS ). 1 Research estimates that 80-90 % of drug substances in development at present may exhibit solubility problems . 2
The discovery , development and manufacturing process for high-quality pharmaceutical products can be a long , challenging and cost-intensive task . Taking a drug to market requires navigating a complex regulatory landscape , and managing various key ingredients and forms , each having different functionality and potential for unwanted interactions during processing , storage , handling , or administration .
For traditional dosage forms , such as oral solid dose , solubility and other drug properties , such as stability , flowability and wettability are key deciders for drug developability performance . Poor water-solubility can have major repercussions for drug efficacy , safety and effectiveness .
When poorly water-soluble drugs are delivered , they fail to dissolve , resulting in severely limited bioavailability , and therefore have reduced therapeutic effect . Furthermore , solubility challenges can impact development timelines and costs , delaying the timely delivery of life-saving medicines to patients .
One challenge , many solutions
To overcome the challenges of poor aqueous solubility and bioavailability , there have been many technological advances . These approaches leverage the physical and physicochemical properties of crystals , and particles thereof , and of APIs and excipients .
Additionally , in recent years , alternative techniques have been developed to increase solubility . These include hydrotropy , selective adsorption or the use of insoluble transporters , and the use of co-solvents , polymeric micelles and nanoparticle formulations , to name just a few .
However , ensuring that final product quality while enhancing drug solubility remains challenging due to the inherent complexities . This arises , in part , from multitudes of components , factors and properties , each having different functionality and safety during processing , storage , handling or administration .
With such a variety of tools and techniques available to drug developers , finding the most effective method for each molecule can be challenging . As such , even with the wide range of tools available to developers today , improving solubility requires the right mix of solid form and particle engineering ( PE ) expertise , manufacturing scaleup know-how , and screening and characterisation technologies to meet the specific characteristics and complexities of each drug candidate .
During early development , one of the main challenges of creating enabling formulations is selecting the appropriate solid form of the drug . At such a stage , a basic understanding of the polymorphism landscape can pay dividends in selecting a ‘ baseline ’ stable form .
Where it is possible , the selection of salts , co-crystals , and amorphous forms can significantly impact the solubility and bioavailability of a
Veranova ’ s SCXRD analysis suite includes a fully automated and highly integrated Rigaku XtaLab Synergy-S diffractometer
drug . And , in some cases , selecting the appropriate solid form can be a complex process that requires a deep understanding of the chemical and physical properties of the drug molecule .
Veranova ’ s Pharmorphix * services are based on over 20 years of solid form and PE expertise in collaboration with in-house physicochemical and analytical services . We use a range of solid form screening and selection processes to choose the preferred salt ( where ionisable centres exist ), co-crystal ( where they usually do not ) and polymorph thereof , or the parent molecule itself , to identify the most suitable solid form for a particular drug .
This is all backed up by robust analytical and physical characterisation and a plethora of supporting data including X-ray diffraction ( powder and single crystal ), thermal analysis , spectroscopy and microscopy , to name a few . The interpretation of this data is key to understanding what it means
20 SPECIALITY CHEMICALS MAGAZINE ESTABLISHED 1981