SSCI may help with many different aspects of solid form screening. Selected from one of topics below for more information.
Addressing Polymorphism: Screening and Characterization
Crystallization of Difficult-to-Crystallize Materials
Selection of Optimum Solid Form of Drug Substance
Chiral Material Analysis
Drug Substance Specifications
Due to regulatory requirements, a comprehensive study of polymorphism is required prior to NDA filing. A comprehensive polymorphism study is necessary for both agency and intellectual property reasons. While necessary, the timing and complexity of the studies are largely set by corporate guidance and perceived best practices.
In recent years, the pharmaceutical industry has continually strived for improved efficiency in screening and selection of not only new chemical entities (NCEs), but also in other areas where automation of process and data collection are appropriate. The role of medium and high-throughput screening in solid-state screening and selection has been hotly debated for the last several years. While SSCI uses high and medium throughput methods for solvent-mediated screening, our data and the data of others (most notably Lian Yu), strongly suggest that simply using solvent-mediated screening will cause the user to miss relevant crystal forms. To that end, a comprehensive and thorough polymorph screening strategy relies on many experimental techniques in addition to solvent mediated experimentation. SSCI's screens are conducted with the widest experimental space available due to the use of common as well as proprietary search mechanisms. Proven to find more forms than standard screening strategies, a typical polymorph screen at SSCI, regardless of scope will utilize:
- Solvent-mediated
- Fast Evaporation
- Slow Evaporation
- Capillary CrystallizationTM (Patent#:USP 6,642,060 and 7,041,169 )
- Mechanical
- Grinding
- Slurry Sonication TM (US Patent Applied For)
- Thermal Techniques
- Computational Pattern Matching and Analysis (USP 7,372,941)
We believe X-ray powder diffraction is the best first pass method to not only discriminate solid-forms but also provide critical data for property determination and structural exploration. Additionally, through the use of SSCI's patented transmission well plates and computational models, we are able to collect data of significant quality 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 material needs of a client, as well as the goals of the screen, SSCI offers:
MicroScreen™
For investigators with only a small amount of sample who need an excellent polymorph screen, MicroScreen™ is the answer. With only 50-200 mg of drug substance, SSCI can carry out an effective polymorph screen and identify the different forms present. Additional material is required to generate scaled-up samples of each form and further analyze them for relative stability and solubility.
Preliminary Polymorph Screen
SSCI has screening services to accommodate different research needs and research budgets. These fast, low-cost screens should be considered if only the more stable forms must be identified and a minimum amount of analytical work be carried out.
Abbreviated Polymorph Screen
Another low-cost, rapid screen, the Focused Screen uses GMP material and process solvents and conditions to identify potential problems associated with manufacturing. It is an ideal screen for manufacturers to check the impact of changes in manufacturing processes or for generic companies to verify solid form behavior under their specific manufacturing conditions.
Standard Polymorph Screen
Our standard screen is designed to identify most of the solid forms of your drug substance. We also scale up each different form, characterize each analytically, and determine relative stabilities and solubilities.
SuperScreen™
A combination of traditional and proprietary technology, SSCI's SuperScreen™ is a comprehensive polymorph screen. We have developed and/or licensed novel proprietary technologies designed to generate new solid forms of materials. The use of these technologies in combination with appropriate traditional crystallization conditions and automation technologies gives us exceptional ability to find the useful forms of your drug substance. We also offer scale-up of all solid forms, analytical characterization, and determination of relative stabilities and solubilities.
SSCI's 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 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.
Poor aqueous solubility is frequently a problem in development of new drug products. One approach that is frequently overlooked is use of an amorphous form of the drug substance. Amorphous materials are generally much more soluble than their crystalline counterparts, and can often be formulated to be physically and chemically stable throughout the shelf life of drug product. SSCI has numerous techniques to search for and stabilize amorphous forms of drug substance.
Cocrystallization is an established technique that is generating renewed interest in the pharmaceutical industry. Cocrystals incorporate guest molecules into a crystal lattice along with the API, changing the physical properties of the solid. SSCI's cocrystal screens can find new solid forms to solve physical property or bioavailability problems or to enable development of improved versions of existing drug products. SSCI has several levels of cocrystal screening to suit different research goals and budgets.
A common occurrence in drug development is poor crystallinity of drug substance. A variety of problems can result from poor crystallinity, including hygroscopicity, poor handling properties, insufficient drug substance purity, and chemical instability. SSCI's crystallization screening strategy relies on the use of a wide variety of crystal growth conditions, often performed using a combination of manual and high-throughput methods. The use of high-throughput technology is typically performed on a case-by-case basis and exclusively in conjunction with manual experiments, recognizing that the search of crystalline seeds for some compounds may not be amenable to high-throughput methods. Alternative methods, such as crystallization via salt or cocrystal formation may also be recommended for the purpose of growing single crystals for structure determination purposes or selection of a solid form for development..
SSCI has extensive experience in solid sample generation from microgram to multi-gram scale. We have expertise ranging 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 important to its efficacy as a drug or excipient are highly dependent on the form of the solid. Is it crystalline, amorphous, a hydrate? To secure FDA approval of an NDA, it is critical to select the optimum solid form for manufacture. SSCI uses a tiered approach to rationally select the optimal form of your specific drug for your specific application. This approach includes salt selection, polymorph and cocrystal screening, and comparative property determinations. Investigations to determine optimal solid form should be carried out as early in the life of a new product as possible. We can work with you to plan a research protocol aimed at selection of the best form of your compound for development and manufacture.
Important thermodynamic properties of polymorphic forms are easily visualized using Energy Temperature diagrams. These diagrams are plots of relative enthalpies and free energies versus temperature. They may be constructed using thermal, solubility, infrared, and/or interconversion data. A diagram of a hypothetical enantiotropic system is shown below. The transition temperature (ttrII→I), the temperature at which relative thermodynamic stabilities change, is clearly indicated on the diagram (Fig 1).
Figure 1: Energy Temperature Diagram of an Enantiotropic System
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 (aka racemate) whereby pairs of enantiomers are present within a single crystal structure, or a conglomerate, constituted of a physical mixture of two crystal phases in equivalent amounts each containing single enantiomers. Use of SSCI's solids analysis capabilities allows determination of these relationships. For example, XRD may be used to determine if a racemic mixture exists as a racemic compound or a conglomerate.
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, SSCI is able to set reasonable and appropriate bulk material specifications. We design methods, carry out sameness testing, and develop and validate quantitative analytical methods to monitor the solid forms of manufactured substances.
SSCI offers screening of resolving agents and design of crystallization processes for the resolution of racemic mixtures via diastereomeric salt formation. Recommendations of resolving agents for screening activities at SSCI are tailored based on the functionalities of our clients' API or intermediate. SSCI's 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.
For more information, Please contact us.