Solid State Chemistry
We are committed to your success in drug substance development through expert solid state chemistry, materials science and engineering principles. Industry leaders in analytical and solid-state chemistry services, our experts screen and select a form with optimal properties and help you understand the processes that ensure consistent material for your development, clinical trials and formulation needs.
Industry leaders in analytical and solid-state chemistry services, our experts screen and select a form with optimal properties and help you understand the processes that ensure consistent material for your development, clinical trials and formulation needs.
With a record of achievement and expert knowledge, our team of scientists delivers meaningful data to our customers in the pharmaceutical, chemical and other industries, where safety and efficacy is critical.
Our skilled scientists become an extension of your team, working in partnership to ensure comprehensive solutions to match your needs in:
- Solid-state chemistry research
- Crystallization process development
- Computational methods
- PAT and QbD processes
Leverage our expertise to select the optimum solid form for drug performance, stability and manufacturability as early in the development process as possible.
Our highly skilled scientists assess the physical properties of your products during pharmaceutical drug development. With access to a comprehensive range of solid form screening solutions, we help optimize solid forms with the desired physical, chemical and biopharmaceutical properties.
We have extensive experience in solid sample generation from microgram to multigram scale. Our expertise ranges from synthesis and salt formation to specialized techniques for making metastable polymorphic forms. We generate and characterize crystalline polymorphs, hydrates, solvates, desolvated solvates, salts and amorphous forms.
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.
We work with you to plan a research proposal aimed at selection of the best form of your compound for development and manufacture.
Our approach includes salt selection, polymorph screening and cocrystal screening, and comparative property determinations.
Salt Screening and Selection
You may wish to use a salt screen due to poor drug substance properties such as lack of crystallinity, water solubility or stability. 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.
Our skilled team designs the salt screen based on the desired improvement 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, our scientists 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 innovative 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 tried and tested 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.
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 it might be 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 skilled scientists design methods, carry out sameness testing and develop and validate quantitative analytical methods to monitor the solid forms of manufactured substances.
We offer sophisticated 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.
We can help you assess the physical properties of your products during pharmaceutical drug development. The physical properties of a solid drug substance are highly dependent on the solid form. By understanding the solid form landscape you can select the optimum solid form for drug performance, stability and manufacturability as early in the development process as possible.
Partner with our experienced scientists and engineers to develop a customized crystallization processes, adapted for each stage of your pharmaceutical development.
Our dedicated group of crystallization experts have a legacy of success in particle engineering and technology transfer. We take a quality- by- design approach to crystallization process development, aiming for the consistent preparation of batches with the desired purity, crystal form and particle properties.
We provide you with highly detailed information about your drug substances to optimize yield, flowability, particle size and/or bulk density and facilitate downstream processing and formulation of your drug product.
Developed in parallel with manufacturing processes, our crystallization services are part of our complete end-to-end service.
Design of Crystallization Process
We expertly apply standard solution crystallization techniques including cooling, antisolvent addition, pH swing, reaction and evaporation.
Our team actively collect metastable zone width information in systems of interest to determine suitable seeding conditions and control strategy. Online and offline monitoring during crystallization may also provide valuable insight into nucleation and growth of the crystals as well as the polymorphic form.
Access to specialized equipment ensures the most comprehensive crystallization process development. Equipment includes:
- Controlled laboratory reactors from 50 mL to 2 L
- Equipment for solubility and metastable zone width determination
- In situ or at-line monitoring of crystal form
- Particle size
Process Analytical Technology and Quality by Design
Our crystallization scientists have access to sophisticated process analytical technology equipment to allow development and optimization of crystallization using a quality- by- design approach:
- Solubility determination capability
- Solvent addition
- Equilibrium solubility with analysis of supernatant by UV-vis, HPLC or UPLC
- Controlled laboratory reactors from 50 mL to 2 L scale
- Mettler Toledo EasyMax™ controlled lab reactors (50–100 mL)
- Radleys Lara™ (100, 250, 500 mL, 1 L and 2 L)
- In situ and offline monitoring
- Mettler Toledo Turbidity Trb 8300
- Kaiser Raman RXN3
- Image analysis
- Vacuum filtration
- Agitated filter dryer (up to 2 L scale)
We can efficiently design, optimize or troubleshoot your crystallization process for product purity, recovery or solids separation and isolation.
Our dedicated experts provide you with an understanding of your process to quickly reduce operational problems by means of:
- Polymorph investigations
- Control and measurement of impurities
- Kinetics of nucleation and growth
- Crystal size distribution measurement and modification
- Habit modification
- Filtration studies
- Drying investigations
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What Everyone Needs to Know about Polymorphs
If you’re involved in late drug discovery, API manufacture, drug product formulation, clinical material production, or manufacture of final dosage form, a basic understanding and awareness of solid form issues could save you a great deal of difficulty, time, and money during drug development.
What is polymorphism?
Polymorphs are crystalline materials that have the same chemical composition but different molecular packing. The concept is well demonstrated by the different crystalline forms of carbon. Diamond, graphite, and fullerenes are all made of pure carbon, but their physical and chemical properties vary drastically. Polymorphs are one type of solid form. Other solid form types include solvates, hydrates, and amorphous forms. Solvates are crystalline materials made of the same chemical substance, but with molecules of solvent regularly incorporated into a unique molecular packing. When water is the solvent, these are called hydrates. An amorphous form of a substance has the same chemical composition, but lacks the long-range molecular order of a crystalline form of the same substance. Many organic and inorganic compounds, including APIs, can exist in multiple solid forms. Some APIs may have only one or two known solid forms. Others may exist in twenty different forms, each having different physical and chemical properties.
Does solid form matter?
Sometimes the properties of two solid forms of a drug are quite similar. In other cases, the physical and chemical properties can vary dramatically and have great impact on pharmacokinetics, ease of manufacturing, and dosage form stability. Properties that can differ among solid forms of a substance include color, solubility, crystal shape, water sorption and desorption properties, particle size, hardness, drying characteristics, flow and filterability, compressibility, and density. Different solid forms can have different melting points, spectral properties, and thermodynamic stability. In a drug substance, these variations in properties can lead to differences in dissolution rate, oral absorption, bioavailability, levels of gastric irritation, toxicology results, and clinical trial results. Ultimately both safety and efficacy are impacted by properties that vary among different solid forms.
Stability presents a special concern, since it’s easy to inadvertently generate the wrong form at any point in the development process. Because energy differences between forms are usually relatively small, form interconversion is common and can occur during routine API manufacturing operations and during drug product formulation, storage, and use. The stakes are high. Encountering a new solid form during late stages of development can delay filing. A new form appearing in drug product can cause product withdrawal.
When should a search for solid forms begin?
The key to speed in the drug development process is to do it right the first time. For solid pharmaceuticals, that means:
- identify the optimum solid form early in drug development
- make the same form for clinical material and commercial API
- develop a crystallization process that assures control of solid form
- produce a drug product with solid form stability through expiration
Our scientists strongly recommend that investigation of possible solid forms of a new chemical entity be carried out as early in the development process as drug supply will allow. The best approach has three stages. The first stage, more relevant to some development processes than to others, is a milligram-scale abbreviated screen on efficacious compounds prior to final IND candidate selection. This early information can be used to guide selection of salts and solid forms for scale-up and toxicology studies. The second stage is full polymorph screening and selection of optimum solid form. This stage is important to all development processes and should certainly occur before the first GMP material is produced. In the case of ionic drugs, various salts should be prepared and screened for polymorphs and hydrates. The third stage, an exhaustive screen carried out before drug launch, is an effort to find and patent all of the forms of a high-potential drug. Staging the screening in this way optimizes the balance among the factors of early knowledge of options, probability of commercial success, and judicious investment of R&D money.
Delay in understanding solid form issues results in problems like different batches of clinical material having different solid forms. Another common and preventable dilemma arises when clinical trials are carried out with one form while commercial production generates another. In this case, bridging studies are required to demonstrate to regulatory agencies that the clinicals are relevant. ICH guidelines require a search for solid forms, comparison of properties that might affect product efficacy, and, if appropriate, setting of solid form specifications.
How is solid form controlled in API manufacture?
It is important to control solid form during API synthesis in order to demonstrate complete process control to regulatory agencies. Different solid forms can have different solubilities and can affect recovery of API. Purification efficiencies can vary due to differential exclusion of impurities. Filtration and transfer characteristics often differ between forms. Ease of drying can vary due to different abilities to bind solvent and water in the crystal lattice.
A prevalent but incorrect belief is that solid form is determined primarily by choice of crystallization solvent. In fact, it is well established that parameters like temperature, supersaturation level, rate of concentration or cooling, seeding, and ripening can have an overriding effect. These variables must be controlled to ensure consistency of solid form in API.
Can solid form problems arise in drug products, too?
The potential for solid form variation does not end at API production. Solid form issues remain through formulation, manufacture, storage, and use of drug product. It is common to observe form transformation during standard manufacturing operations like wet granulation and milling. Excipient interactions and compaction can induce form changes. Changes can occur in the final dosage form over time. Suspensions, including those in transdermal patches, are particularly vulnerable because they provide a low-energy pathway (dissolution/recrystallization) for form interconversion. Lyophile cakes are normally amorphous, but can crystallize on storage leading to difficulty in reconstitution. Even products containing drug in solution, such as filled gel caps, can be affected if the solution is or becomes supersaturated with respect to one of the possible solid forms of the drug.
How can you tell when you have a solid form problem?
Whenever there is a specification failure in drug product or drug substance, solid form changes should be considered in the search for causes. Particularly symptomatic is failure to meet melting point or dissolution specifications. Changes in humidity, crystallization conditions, or crystallization solvent can produce unwanted forms. Solvents known to readily produce solvates include water, alcohols, chlorinated hydrocarbons, cyclic ethers, ketones, nitriles, and amides. Changes in the appearance of gel caps or cracking of tablet coatings can indicate solid form problems. Various solid-state analytical techniques can be used to identify solid form in API. Some techniques can even determine solid form of API in intact final dosage form. Among the most useful techniques for solid-state characterization are melting point, DSC, TGA, hot stage and optical microscopy, solid-state NMR, IR and Raman spectroscopy, and X-ray powder diffraction.
Is there any good news about polymorphism?
Polymorphism presents opportunities as well as challenges. Investigation of the properties of different forms of a commercial drug can lead to new products with improved onset time, greater bioavailability, sustained release properties, or other therapeutic enhancements. New forms can bring improvements in manufacturing costs or API purity. These improvements are patentable and can provide a competitive advantage. An underutilized potential of polymorphism is to solve formulation problems that cause the abandonment of potentially useful drugs in which much investment has already been made.
Our mission is to help you accelerate regulatory approval and reduce time to market.
With extensive experience in cGMP solid state research and analysis, we help you meet your process analytical technology (PAT) challenges, ensuring consistent product quality and streamlining your PAT implementation.
Our rigorous PAT approach is consistent with the FDA perspective that quality cannot be tested into products, but should be built in. The end-to-end service we provide is underpinned by quality at every stage, we support the development and optimization of your compound using a quality by design (QBD) approach.
We routinely achieve improved quality and efficiency through:
- Reduction of cycle times using on-, in- or at-line measurements and controls
- Prevention of reject product and waste
- Real-time product release
- Increased use of automation
- Facilitation of continuous processing using small-scale equipment, resulting in improved energy and material use and increased capacity
We have extensive experience solving solid state problems in drug products and bring exceptional skill to the analysis and control of complex attributes such as solid form, particle size and particle shape.
Our highly skilled computational scientists can derive more information than you ever thought possible from laboratory X-ray powder patterns. If you have a mixed powder of unknown solids we apply our innovative tools to analyze and separate the individual crystal structures in your drug substance or product.
Our experts have developed unique software capable of rapidly providing accurate structural information from standard laboratory X-ray powder diffraction (XRPD) data. This powerful technique is used to determine the structure of crystalline solids.
Our ingenuity enables us to quickly obtain structural information such as correct unit cell parameters, molecular packing information and electron density distribution within the unit cell. We leverage this information to speed your drug development and address manufacturing issues for your drug substance and drug product.
Information From XRPD Data
Our new innovative technique offers the following benefits:
- Unit cell parameters, molecular packing and electron density distribution
- Prediction of density, stability, hygroscopicity and other properties
- Analysis of microstructure, average crystal size and strain
- Analysis of X-ray amorphous materials and determination of their crystalline parents
- Distinction between true amorphous and disordered crystalline materials
- Quantitative (cGMP) and semi-quantitative (non-GMP) mixture analysis
Custom Development Services
We work in partnership with our clients and appreciate that a customized approach may be needed to achieve your goals. We offer project-based custom software development and analytical instrumentation improvement in our areas of expertise, including automation, XRPD and Raman.
Our scientists help you get the most out of your existing X-ray diffraction systems by improving data quality and productivity.