Our scientists offer numerous types of solid form screening.
A comprehensive study of polymorphism is required prior to NDA filing and is also necessary for intellectual property reasons. The pharmaceutical industry strives for improved efficiency in screening and selection of new chemical entities and in other areas where automation of process and data collection are appropriate.
To that end, an effective polymorph screening strategy relies on many experimental techniques in addition to solvent-mediated experimentation. We conduct our screens with the widest available experimental approaches, using common as well as proprietary search mechanisms. Proven to find more forms than standard screening strategies, our typical polymorph screen will employ:
- Solvent-mediated screening
- Fast evaporation
- Slow evaporation
- Mechanical techniques
- Thermal techniques
- Computational pattern matching and TRIADS indexing analysis (U.S. Patents 7372941 and 8576985)
We believe X-ray powder diffraction is the best first method to discriminate solid forms and provide critical data for property determination and structural exploration. Additionally, by applying our computational models, we collect high-quality data to develop a deep structural understanding of the solid forms present and predict properties including relative thermodynamic stability, habit, density and electron density.
Based on the time and materials available, we offer a variety of screen types, which we tailor to your specific needs.
|Crystallization screen||Identify a crystalline form for development or purification purposes for hard-to-crystallize compounds.|
|Discovery screen||Identify a solid form with fit-for-purpose properties and assess the associated risks.|
|Enabling form screen||Identify the most stable form as well as conduct optional screening to estimate the type and number of different solid forms possible, including polymorphs and hydrates/solvates.|
|Process crystallization screen||Identify crystalline forms relevant to process in place to mitigate risk in a process.|
|Standard or comprehensive screens||Identify as many solid forms as possible; may include salts/cocrystals to support client-defined intellectual property strategy.|
Salt Screening and Selection
Our salt screen involves a search for solid salts of ionizable drug products using sources of pharmaceutically acceptable counterions as well as knowledge of their properties, frequency of use in drug products and manufacturability. The desire to use a salt screen is usually due to poor drug substance properties such as lack of crystallinity, water solubility or stability. We design the salt screen based on the improvement desired and properties of the API, often using a tiered testing procedure to quickly identify the salts with optimum properties.
Solid Dispersion Screen
Poor aqueous solubility frequently occurs during the development of new drug products. To address solubility issues, we employ numerous techniques to search for and stabilize amorphous forms of drug substance. Amorphous materials are generally much more soluble than their crystalline counterparts, and we can often formulate them to be physically and chemically stable throughout the shelf life of the drug product.
Cocrystals incorporate guest molecules into a crystal lattice along with the API, changing the physical properties of the solid. Our cocrystal screens can identify new solid forms to solve physical property or bioavailability problems or to enable improved versions of existing drug products. We offer several levels of cocrystal screening to suit your research goals and budgets.
Crystallization of Difficult-to-Crystallize Materials
A common occurrence in drug development is poor crystallinity of a drug substance. A variety of problems can result from poor crystallinity, including hygroscopicity, poor handling properties, insufficient drug substance purity and chemical instability. Our crystallization screening strategy relies on the use of a wide variety of crystal growth conditions. We may also recommend alternative methods, such as crystallization via salt or cocrystal formation, for the purpose of growing single crystals for structure determination purposes or selection of a solid form for development.
Selection of Optimum Solid Form of Drug Substance
We have extensive experience in solid sample generation from microgram to multigram scale. Our expertise ranges from synthesis to salt formation to specialized techniques for making metastable polymorphic forms. We generate and characterize crystalline polymorphs, hydrates, solvates, desolvated solvates, salts and amorphous forms.
The properties of a solid that are important to its efficacy as a drug or excipient are highly dependent on the form of the solid. To help you secure FDA approval of an NDA, we use a tiered approach to select the optimal form of your specific drug for your specific application. Our approach includes salt selection, polymorph screening and cocrystal screening, and comparative property determinations. We can work with you to plan a research proposal aimed at selection of the best form of your compound for development and manufacture.
Thermodynamic Property Studies
We can help you easily visualize thermodynamic properties of polymorphic forms by using energy temperature diagrams. These diagrams plot relative enthalpies and free energies versus temperature. They may be constructed using thermal, solubility, infrared and/or interconversion data.
Chiral Material Analysis and Resolution
Like polymorphs, solid forms attained from racemic mixtures of a given chiral compound can be crystallographically distinct. A racemic mixture in the solid form may exist as a racemic compound (a racemate) whereby pairs of enantiomers are present within a single crystal structure, or a conglomerate, constituted from a physical mixture of two crystal phases in equivalent amounts, each containing single enantiomers. Our solids analysis capabilities enable determination of these relationships.
Drug Substance Specifications
The specifications established for bulk materials are crucial in designing appropriate analytical and quality control methods. By determining the properties and relative stabilities of solid forms, we set reasonable and appropriate bulk material specifications. Our scientists design methods, carry out sameness testing and develop and validate quantitative analytical methods to monitor the solid forms of manufactured substances.
We offer screening of resolving agents and design of crystallization processes for the resolution of racemic mixtures via diastereomeric salt formation. Our experts tailor recommendations of resolving agents for screening activities based on the functionalities of your API or intermediate. Our combination of solid state techniques and chiral chromatography capabilities allows for effective screening, selection and process development activities to deliver a scalable procedure for the resolution of racemic mixtures.