Solid Form Screening and Selection

Solid Form Screening and Selection 2018-07-11T15:23:45+00:00

SSCI may help with many different aspects of solid form screening. Selected from one of topics below for more information.

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.

Addressing Polymorphism

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 has used 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 available experimental space using common as well as proprietary search mechanisms. Proven to find more forms than standard screening strategies, a typical polymorph screen at SSCI, will utilize:

  • Solvent-mediated
  • Fast Evaporation
  • Slow Evaporation
  • Mechanical
  • Grinding
  • Thermal Techniques
  • Computational Pattern Matching and TRIADS Indexing Analysis (US Patents 7,372,941 and 8,576,985)

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 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 materials available, as well as the goals of the screen, SSCI offers a variety of screen types outlined in the table below which are tailored to the specific needs of a client.

Screen Type Description
Crystallization Screen Identify a crystalline form for development or purification purposes for hard-to-crystallize compounds.
Discover 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 optional screening to provide an estimate of 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 for the purpose of de-risking a process.
Standard or Comprehensive Screens Identify as many solid forms as possible, may include salts/cocrystals, to support client-defined intellectual property strategy

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Salt Screening and Selection

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.

Solid Dispersion Screen

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.

Cocrystal Screen

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.

Crystallization of Difficult-to-Crystallize Materials

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. 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.

Selection of Optimum Solid Form of Drug Substance

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.

Thermodynamic Property Studies

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


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 (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.