Tips and Tools from Syntagon

Solid-state Development: Recommendations for Phase I


Introduction

A well-performed solid-form screening and development will impact on pharmaceutical properties of an API such as bio-availability, stability and process-ability as well as physicochemical properties such as physical and chemical stability, solubility, dissolution rate, hygroscopicity, crystal form and mechanical properties. The solid form screening and the process of optimal form selection with desirable physical properties are also crucial not only for formulation but also for patent protection and regulatory filing.

However, the fact that crystalline solids exist as polymorphs, solvates/hydrates, salts or co-crystals poses both opportunities and challenges. Drawing on years of experience in assisting companies of various sizes with their drug development programs, Syntagon shares five reflections for improving solid-state programs when moving from pre-clinical to clinical development:

  • Select an optimal salt or neutral form early
  • Do a limited polymorph analysis for Phase I
  • Protect your IP
  • Work with experts
  • Consider co-crystallization


Select an optimal salt or neutral form at an early stage

When producing material for Phase I and toxicological studies, we recommend that a salt screen is performed before or in parallel with the development of manufacturing methods for Phase I production.  Screening for optimal salt form at an early stage will enable the right salt be found while allowing purification and filtration methods to be developed in parallel without changing the impurity profile.   Changing your salt form will therefore change your drug characteristics, and most likely the impurity profile of your API. If the new salt form, with improved drug characteristics, is found in a screen conducted after your phase I study, this might force you to delay filings .


Do a limited polymorph analysis for Phase I

An important aspect of drug development is the study of the polymorphic behaviour of your API. Polymorphism can be described as the ability of a substance to exist as more than one crystalline phase, where the phases may include molecules of different arrangements and/or conformations in the crystal lattice. The various crystalline forms may show remarkable differences in physical properties such as colour, solubility, dissolution rate, stability, water sorption/desorption behaviour, crystal shape, surface and mechanical properties, many of which may be central to the design, manufacture and performance of a formulation.

For Phase I, we recommend performing a limited polymorph screen, a balanced resource and a risk-based strategy . The long-term physical stability of an API may not be a concern for Phase I, as the formulations for this phase in general are simple and administered either on-spot or with minimal storage time.   A more thorough study is instead recommended for Phase II.


Protect your intellectual property (IP) rights

Only identified and sufficiently characterized polymorphs and salt forms will be individually protected by patents. Therefore, regardless of whether you intend to protect or circumvent a patent, the outcome of your solid-state study will significantly impact your intellectual property rights.


Work with experts

Crystallization is still an art form that requires great practical, hands-on skill as well as extensive scientific knowledge. At Syntagon, our strategy is to ensure that leading experts are dedicated to your crystallization and solid-state development projects.

With our hands-on approach observations and conclusions are made not only before and after an experiment, as when using a typical 96-well approach, but throughout the development process. In this way, a wealth of valuable information will be retrieved and used for designing new experiments, while less successful experiments can either be stopped or adjusted at an early stage. Much of this information can also be useful later be useful later in process development and up-scaling.

Although using a machine can save both time and materials, we have followed this approach for more than twenty years, and are certain that it provides the best results.  

Our solid-state experts include:

Karol Horvarth specializes in crystallization of substances with particular emphasis on preparation of salts and polymorphism studies. He has over 20 years of experience in crystallization and salt screening and has developed new techniques, solved more than 200 crystallization problems, and holds a range of patents on crystallization. 

Sitaram Velaga is an associate professor of pharmaceutics at Luleå Technical University.  He specializes in solid-state research, particularly in co-crystallization and polymorphism in drugs. He has produced an extensive list of peer-reviewed publications and has spoken at a large number of international conferences.


When standard techniques are not enough… consider co-crystallization and Colloidal dispersion.

For small molecular APIs, many techniques are available to obtain crystals. Most of them involve changing crystallization parameters such as temperature, evaporation rate, and the addition of an appropriate anti-solvent. In some cases, particularly for larger, more complex structures, attempts at crystallizing a compound can yield an oily phase, instead of crystals. In these cases, experience has shown that crystallization via colloidal dispersion (CCD) can be utilized. This method is based on very high super-saturation and normally involves the use of three solvents: A good solvent, an anti-solvent and a poor solvent (a so-called solvent modifier). For more information about this technique, please click here. 

Another solid-state technique of considerable interest and great promise is co-crystallization when faced with the following challenges in drug development: 1) the API is neutral and therefore not suitable for salt formation; 2) the API is not crystalline; and/or 3) physical property improvement by other technologies is marginal. In addition, pharmaceutical co-crystals broaden the solid form diversity for an API and offer IP possibilities just as salts do. Pharmaceutical co-crystals are homogeneous crystalline materials comprising two components (API plus co-crystal former) that are solids at room temperature in a stoichiometric ratio. 


Summary

Since most drugs are administrated as solids, solid-state forms show different physical properties such as solubility, dissolution rate and stability which will have significant implications on the design, manufacture and performance of a dosage form. In addition, new solid forms offer additional protection for your intellectual property rights.

Because a change in salt implies a change in the resulting drug, a detailed salt screening study performed in parallel with the manufacturing methods for Phase I production is recommended. The polymorph screen, however, should be performed in two steps: A limited polymorph screen for Phase I, and a more detailed study for later stages of development.

When it is not possible to crystallize or form a salt of your drug substance by using standard techniques, Syntagon offers other proven methods such as crystallization via colloidal dispersion and co-crystallization.

Syntagon has chosen to work with actual experts instead of machines, allowing us to tailor our strategies according to the unique features of your API. Having followed this approach for more than ten years, we know that it provides the best results.