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Parallel Screening

Improving the bioavailability of poorly soluble new chemical entities is a leading challenge in drug development. Parallel screening is a cost-effective concept for selecting a suitable drug delivery system to enhance the chance of achieving the bioavailability target in the clinic.

One of the biggest challenges faced by pharmaceutical scientists is poor solubility and bioavailability of new molecular entities (NMEs). Researchers often find promising candidates in drug screening, but if the molecule is ‘brick dust’ the chance of delivering it to the site of action is diminished.The undesirable low solubility of candidates is placed on the modern drug discovery process where combinatorial chemistry and highthroughput screening are used to select compounds based on their affinity to bind to the targets.As a result, the molecules have shifted towards higher molecular weights and lipophilicities, and less soluble and less permeable (1,2).These challenging compounds belong to the Biopharmaceutical Classification System (BCS) II and IV due to their poor solubility and/or permeability, and thereby poor bioavailability (see Figure 1) (3). Literature shows that there is an increasing number of poorly soluble compounds in the drug discovery pipeline – including 70 per cent BCS Class II compounds – although only about 30 per cent are BCS Class II in the existing top 200 market (see Figure 2) (4). The current discovery programmes have the potential to create a significant loss of economic and therapeutic opportunity due to product attrition resulting from poor bioavailability.

 

Applying suitable technologies and approaches to increase the bioavailability of poorly soluble molecules will reduce the attrition rate, increase the number new drugs getting to the market and consequently bring better healthcare to patients.

Bioavailability improvement is a multifactorial challenge and is determined by several factors, including API properties, formulation and delivery technology, and GI kinetic and physiology. Suitable technologies must address these factors in order to achieve the objectives. Common delivery technologies that have been utilised for improvement of bioavailability of poorly soluble compounds are provided in Figure 3.They may be classified as size reduction, solubilisation, and solid dispersion techniques.



Unfortunately, pharmaceutical companies have adopted different paths based on available technologies, often in series, to manage bioavailability issues at an early stage in the drug discovery and proof-of-concept stages. Following this approach through in-house efforts or via contracting to development service organisations to evaluate individual techniques in this fashion have resulted in significant investment of time and money (see Figure 4). 



Parallel Technology Screening

A parallel approach has been designed to speed the screening of lead candidates and identify the technique to progress the molecule to a proof-ofconcept stage. Parallel screening speeds the discovery and development of potential drug candidates.

A parallel screening programme should begin with an upfront scientific assessment to define potential technology solutions followed by the application of a series of screening tools to fine tune strategy and define prototype compositions.Next, the preparation and evaluation of pilot formulations is carried out using miniaturised equipment and predictive methods before animal pharmacokinetic studies.The results are expected to enhance the probability of successfully developing suitable clinical formulations for BCS class II and IV compounds in FIH and proof-of-concept studies (see Figure 5). 



Upfront Scientific Assessment

The bioavailability of an orally administered drug is dependent on the concentration of the dissolved drug at the site of absorption, GI permeability, absorption window, metabolism, elimination and dose administration. These physical and physiological events are influenced by the inherent API biopharmaceutics, drug substance physicochemical properties and applied delivery technology.With an upfront assessment, it is often possible to identify promising delivery solutions and approaches for screening, although a paper exercise alone is not likely to succeed given the complexity and integrated nature of the physical and biological systems. Scientific assessment also helps define the scope and timeline for the parallel formulation screening programme. 

Using griseofulvin as an example, the solid state properties, biopharmaceutics and available delivery solutions are considered in a scientific assessment. Griseofulvin is an antifungal agent with a strong crystal lattice that is reflected by high melting point and poor solubility in both polar and non-polar solvents (log P about 2).The molecule has several polar functional groups, although it is not ionisable; it is a BCS II compound with an orthorhombic well-packed crystal lattice (no polymorphs are reported to date). Griseofulvin is administered at one gram per day. In view of the solid-state properties and biopharmaceutics, micronisation can be included in the screening because of the high melting point and well-formed crystal structure. Other delivery systems, such as high energy milling to produce submicron particles and solubility enhancement by solid dispersion,may also be considered to improve the bioavailability. However, the strong crystal lattice suggests that griseofulvin is susceptible to Ostwald ripening in suspension or crystallisation in solid dispersion. A suitable crystallisation inhibitor(s) is also recommended. For drug delivery by solubilisation, both highly polar and non-polar solvents should be avoided. The solubility will likely be improved in solvent systems with a combination of Debye interactions, dispersion forces and specific molecular structures.The relatively high dosage and low solubility suggest that the development of a liquid-filled capsule for griseofulvin will be challenging. 

Parallel Screening Tools

A number of established screening studies – including thermal analysis, optical microscopy and spectroscopic methods, targeted solid-state characterisation, solubility studies and permeation studies (for example, bi-directional Caco-2 assay) – can be applied to collect data to fine tune delivery strategies and define prototype compositions. For example, based on the molecular structure and properties of the API and polymers, experiments can be designed to produce solid dispersions using milligram quantities of API and excipients in a differential scanning calorimeter (DSC) (see Figure 6). In general, an excipient screening programme using DSC can be completed within a few days to identify several lead solid dispersion formulations. Other excipient screening studies such as preparation of simple quaternary phase diagrams followed by dilution tests may be employed to define compositions and to predict the in vivo behaviour of self emulsifying drug delivery systems (SEDDS). Effective use of screening tools reduces or eliminates trial-and-error in prototype preparations. It also creates improved design spaces to improve the probability of success downstream in vitro and in vivo.



Preparation of Pilot Formulations

A balanced approach to produce pilot formulations using miniaturised API sparing equipment and methods is often cost-effective and time-saving. The choice of equipment and methods depends on their capability to ‘get the job done’and the operating principle. It is common to prepare simple liquids and powder blends using manual operations for formulation testing and animal studies. In the case of preparing solid dispersions, a slow bench top solvent evaporation process may not produce a physically stable product, whereas a mini-spray dryer may produce a formulation that improves bioavailability. Spray drying is known to be fairly scalable, albeit generally expensive and employs organic solvents. 

An array of predictive methods can easily be utilised to test and select pilot formulations for bioavailability studies. Optical microscopy is a simple technique to study particle size and habit of powders. It is also a quick, complimentary technique to x-ray diffraction to reveal the presence of crystalline (versus amorphous) materials (see Figure 7). Modified dissolution testing (paddle) and micro centrifuge dissolution will provide the API release characteristics at normal and supersaturated conditions in a bio-relevant medium as required for a wide range of prototype formulations. Monitoring particle size as a function of time is useful for studying crystal growth or changes in nano-suspensions or emulsions.Thermo analysis provides solid state, solid form and physical stability information, for example based on glass transition temperature of solid dispersions, for formulation assessment and animal pharmacokinetic formulation selection.

Animal Pharmacokinetics Studies and Clinical Formulation Development

Based on the data collected in the parallel screening programme, suitable formulations are studied in defined animal species (see Figure 8).The choice of animal model and the bioavailability study design depend on the physical properties and pharmacokinetics of the API, as well as the animal GI physiology and metabolism. A technical recommendation for the development of clinical formulation(s) is expected to be available after the in vitro/in vivo performance, biopharmaceutics of the molecule, clinical indication and complexity of formulation, manufacturing, or scale-up of the delivery technology are considered.



Conclusion

Improving solubility and bioavailability is a multifaceted challenge in the drug development process. Many technologies exist with varied degrees of success; so selecting and employing the most appropriate technology is often required to achieve the development goals.

Evaluating any set of technologies in sequence can be very expensive, timeconsuming and a serendipitous exercise. A parallel screening approach with an upfront scientific assessment can be a powerful tool and provide fast, costeffective results with better chances of success. Integration of animal pK evaluation provides the set of data to give a quick feedback to decide a path forward. Accelerated development through parallel screening could lead to a faster and more effective path to FIH trials.

References

  1. Lipinski CA, Drug-like properties and the causes of poor solubility and poor permeability, J Pharmacol Toxicol Methods 44: pp235-249, 2000
  2. Lipinski CA, Avoiding investment in doomed drugs, Curr Drug Discov 1: pp17-19, 2001
  3. Amidon GL, Biopharmaceutics classification system: Interview with Professor Gordon Amidon, Dissoln Tech, November 1998
  4. Hauss D, Oral lipid-based formulations: enhancing the bioavailability of poorly water-soluble drugs, Marcel Dekker, 2007

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Kwok Chow is the Senior Director of Global PDS Technology and Alliances at Patheon Inc. He has a BS Pharm from the University of Minnesota and a PhD in Physical Pharmacy from Professor David Grant at the University of Toronto. Kwok has more than 20 years of global CMC experience in leading early and late development as well as line extension projects. He is also a specialist in solid-state characterisation, material science and drug delivery technologies.

Anil Kane is presently the Senior Director of Pharmaceutical Technical Affairs, North America, in the Pharmaceutical Development Services Group of Patheon Inc, a contract pharmaceutical development and manufacturing service provider. He received his Bachelors, Masters and PhD degrees from the University of Bombay, India and was a post-doctoral fellow at the School of Pharmacy at University of Cincinnati, Ohio. Anil has an executive MBA from Richard Ivey School of Business, University of Western Ontario in Canada. Anil has over 25 years of experience in product development and has been involved in taking molecules from early stage development to scale up, technical transfers between various manufacturing sites around the world and drug lifecycle management.
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