Crystal Structure Determination

Physicochemical Profiling

Physicochemical properties investigations are vital for the development of any robust crystallization process and formulation. TeraCrystal scientific team identifies fit-for-purpose characterizations for drug molecules and selected solid forms, to assess potential development risks. Subsequently, we direct the choices towards the most appropriate crystallization processes. Our services include:

The solid form properties of a promising active pharmaceutical compound, like crystallinity, polymorphism and selected form (free acid/base or salt) can drastically alter physical and chemical stability, effectiveness and processability for a particular formulation. These basic criteria are crucial in order to facilitate a successful development all the way to a product on the market.

Therefore, finding the “right”, the most suitable solid form and assuring that it is fruitfully delivered is part of an integrated approach to solid-state issues, offered to our clients.

We design fast turn-around tailored packages of solid state studies for small organic molecules and peptides to identify the best solid forms, polymorphs, salts/co-crystals and amorphous dispersions, to overcome developability issues and enhance the intellectual property rights over a compound.

  • Solubility – solubility in process solvents, pH solubility profiles, purity profile.
  • Dissolution – dissolution rate, powder/drug product, in aqueous and biorelevant media.
  • Stability – hygroscopicity, hydration propensity, stable vs. metastable, phase diagram.
  • Water content determination of hydrate stoichiometry by Karl Fisher method.
  • Particle engineering characterization of particle morphology and particle behavior during processing.
  • Polymorphic Phase transition – determination of inversion point and interconversion parameters.
  • pKa/LogP/LogD – we provide full scientific support for data interpretation and for any additional details our customers would need.

Crystallization Process

Our solid form programs can easily progress into crystallization process development studies, scaling the selected solid forms from milligram to multigram scale in preparation for further manufacturing. Critical parameters for crystallization, such as yield, chemical purity, polymorphic purity, solvent class (according to ICH guidelines), residual solvent content are monitored. Obtaining a crystalline material with a consistent particle size and morphology (external shape, habit) is also important.

Additionally, we have extensive experience in collecting metastable zone width information, testing process robustness and optimization of crystallization parameters, according to polymorphism, solubility, supersaturation, nucleation and growth.

Preformulation

At TeraCrystal, we have strong scientific expertise that cover all pre-formulations services including:

  • Physical and Chemical stability on storage – accelerated conditions according to the ICH guidelines.
  • Excipient compatibility – assessment the stability of a drug candidate with commonly used pharmaceutical excipients in various accelerated stability conditions.
  • Formulation design for poorly soluble compounds.
  • Formulation screening to overcome solubility, precipitation, dissolution rate, and wettability issues.
  • In vitro dissolution of prototype formulationcharacterizes how an API is extracted out of a solid dosage form.
  • Blend and tablet homogeneity – content uniformity analysis.
  • Mechanical stress – grinding and compression.

Peptide Crystallization

In addition to our small molecule solid form screens, TeraCrystal offers peptide crystallization services.

In order to prevail the difficulties traditionally associated with peptides (molecular flexibility and size) we employ a step-wise strategy, consisting of:

  • Solubility evaluation
  • Small scale crystallization
  • Data collection and analysis
  • Crystal growth and structure determination
  • Identification of critical crystallization parameters
  • Scale up at g scale

At the end of the program we provide our client with crystalline solid of their peptide and a robust gram scale crystallization process.

Key Analytics

At TeraCrystal, we understand that a successful development of drug substance requires sensitive and specific analytical techniques for chemical and physical properties determination.

Our highly skilled scientists are able to pursue studies that range from routine to highly complex and challenging characterization analysis, such:

  • X-Ray Powder Diffraction – XRD – crystallinity, form identification and purity, amorphous content, structure determination.
  • Single Crystal X-Ray Diffraction – SC-XRD – solving crystal structure from crystals and powders, in problematic cases.
  • Solid State-Nuclear Magnetic Resonance spectroscopy-SS-NMR – crystallinity, disorder and polymorphic purity.
  • Nuclear Magnetic Resonance spectroscopy (liquid) – NMR – determination of molecular structure and purity.
  • Transmission Electron Microscopy – TEM – determination of surface morphology.
  • X-Ray Photoelectron Spectroscopy – XPS – determination of chemical composition and chemical state of the compound.
  • Infrared spectroscopy – IR – Identification of compounds, quantification of content and characterization of interactions in mixtures.
  • Raman spectroscopy – Polymorph identity and content, amorphous content, distribution of formulation components.
  • Raman mapping – identification of the chemical identity and location of APIs and excipients within the formulated products.
  • X-ray fluorescence – XRF – determine the elemental composition of APIs.
  • Differential Scanning Calorimetry DSC – API’s thermal behavior, e.g. melting temperature, glass transition temperature, crystallization temperature, solid state transitions etc.
  • Thermal Gravimetric Analyze TGA – determination of change in weight as a response to change in temperature: quantification of residual solvents, phase transition and thermal decomposition.
  • Vibrational Circular Dichroism – Proteins structure characterization: protein folding, protein conformation, DNA/RNA interactions, enzyme kinetics.
  • Dynamic Vapor Sorption – DVS – evaluation of hygroscopicity, water sorption behavior at different relative humidity’s, deliquescence, hydrate characterization, amorphicity etc.
  • Brunauer, Emmett, Teller BET – determination of specific surface area on powders (using N2 adsorption at the temperature of liquid nitrogen). Determination of micropore volume and mesopore distribution of solid samples.
  • Karl Fischer water content up to 5%w; determination of hydrate stoichiometry.
  • Laser Light Scattering – determination of particle size distribution for powders or suspensions using laser diffraction. Particle size (0.4 – 2000 µm).
  • Dynamic Light Scattering – determination of size and size distribution profile of small particles (<1 nm-10 μm), proteins, nanoparticles, polymers and colloidal dispersions.
  • Scanning Electron Microscopy – SEM&EDS – high magnification microscopy with potential for simultaneous elemental analysis using EDS (Energy Dispersive Spectroscopy).
  • EDS Mapping: Samples imaged by scanning electron microscopy (SEM) can be analyzed for elemental composition by energy dispersive spectroscopy (EDS). In an EDS map, a point or pixel can represent an area as small as 2 μm, and more than 20 elements can be mapped simultaneously.
  • High-Performance Liquid Chromatography – HPLC – used to identify, quantify and separate, each component in a mixture.

TeraCrystal core services:

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