Pharmorphix^® Solid Form Modification

It is now recognized that developing an in-depth understanding of the solid form characteristics of small molecule drug compounds is integral to the successful development of tomorrow’s new medicines. By modifying the salt form or polymorph of a drug candidate it is possible to influence physical properties such as dissolution rate, melting point and stability.

Selection of the optimum salt or polymorphic form can also aid in the synthesis, isolation and formulation of the final drug product. It is therefore essential that any candidates entering or progressing through clinical development have been subject to a vigorous and comprehensive salt and polymorph screening program.

At SAFC Pharma's Pharmorphix technology lab system, the importance of scientific input in experimental design and the interpretation of resulting data is never underestimated. In our screening programs it is the science that drives the technology platform in which both manual and focused parallel arrays are commonly used to achieve the desired goal. The application and limitations of high throughput automation in solid form screening is also understood and is only utilized in projects where it will deliver significant results.

There is also an underlying philosophy to deliver client solutions rather than the simple presentation of collected data. From the outset of every study, assigns a dedicated project team is assigned to work closely with the client to determine their exact requirements, designing work programs that are suitable to their particular need at their current stage of development. eRooms are widely used, enabling confidential data to be securely and efficiently transferred to the client.

The objectives of any salt selection program can vary dramatically and is influenced by a wide range of factors such as the therapeutic target, mode of administration and dosage regimen. The ability to prepare the selected salt form in high yield, purity and as a consistent polymorph must also be seriously consideration.

The recommendation to move forward with a particular salt form can have a major impact on the downstream production, formulation and ultimately the likelihood of the candidate being approved as a commercial drug product. No single approach to salt screening will consistently yield the high quality results that are required and a customized approach should be developed for each compound. SAFC Pharma's Pharmorphix team has the flexibility and expertise to perform a variety of screening programs. Studies range from enabling screens performed in parallel on multiple discovery compounds to assisting in candidate selection through to comprehensive studies on commercial products designed to identify new salt forms for use in alternative formulations.

Before engaging in any screening study, careful consideration is always taken in the selection of suitable counterions and is based on a number of factors such as the drug indication, delivery method and the pKa of the active candidate. We always determine the pKa of any candidate entering into salt screening study experimentally as it is not uncommon to observe significant differences between the experimental and calculated pKa values, which can in turn influence the choice of counterions that can be included in any screen.

The SAFC's Pharmorphix team has developed proprietary capabilities which enable us to efficiently screen a wide selection of pharmaceutically acceptable counterions and crystallization methods. Our automated arrays have been specifically designed to maximise the amount of data that can be obtained from each experiment, thereby reducing material consumption. High throughput X-ray diffraction and other complementary techniques are used to characterize all solid materials that are isolated from the screening studies. Any promising salts are therefore rapidly identified, allowing our scientists to focus on those salts from which is it believed a suitable candidate can be selected.

Our comprehensive toolbox of in-house solid state and analytical capabilities allows us fully characterize the properties of each salt form, probing a wide spectrum of physical and chemical properties such as moisture stability, solubility, particle size and dissolution rate. The selection process uses an iterative ranking method that eventually leads to the selection of the preferred candidate. Once the favored solid form has been chosen, our experience in process chemistry allows us to identify protocols for reliably producing the desired final form on scale up.

The influence of polymorphism on the performance and developability of small molecule active ingredients has received significant coverage in recent years. It is now well recognized that a change in the polymorphic form of an API can have far reaching consequences in drug development, impacting on everything from bioavailability to stability in addition to posing significant challenges in both API manufacture and downstream formulation. It is therefore vital that an understanding of the polymorphic landscape is developed to ensure that the optimum crystalline form is developed that displays the required balance of pharmacological and solid state properties.

SAFC Pharma® recognizes that the objectives of a polymorph screen can also vary greatly. We have therefore developed a multi-tiered platform that enables studies to be individually tailored to the needs of each client.

For compounds that are in the early stages of development, studies are usually designed to mimic typical manufacturing and formulation environments. By understanding the impact of factors such as solvent, temperature, humidity and grinding on polymorphic form, it is possible to define the parameters that minimize the risk of preparing unwanted polymorphs. For late stage materials or commercial products there is a greater emphasis on patent protection and life cycle extension. For these studies, parallel arrays and high throughput methodologies are utilized along with environmental stressing such as variable temperature and humidity studies to efficiently screen a larger number of experiments and parameters. The ultimate aim of any polymorphism study is to construct a form, diagram that shows the interrelationships and relative stabilities of each distinct crystal form which can include anhydrous polymorphs and distinct solvated species.

Cocrystals have recently generated huge interest in the pharmaceutical and academic communities as they potentially offer another method of being able to modify the physico-chemical characteristics of an API. By incorporating a cocrystal partner into the crystal lattice alongside the API, it is possible to affect properties such as dissolution rate, stability and melting point as well as formulation related parameters such as compressibility. Although the ability to predict, design and ultimately prepare cocrystals it still at an early stage of development, we work at the cutting edge of this field, constantly evaluating new technologies that allow to us prepare, identify and characterize new cocrystal entities.

The ability to prepare cocrystals in significant quantities is one of the major challenges that still need to be overcome in order for this field to become economically viable method of producing new drug products. Our Pharmorphix laboratories ivestigates how both traditional and new methodologies can be employed to overcome these problems.