Drug Substance
- Why investigate the solid-state of your drug?
- Polymorphism
- Regulatory Aspects
- 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
The properties of a solid important to its efficacy as a drug or excipient are highly dependent on the form of the solid. 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. SSCI can work with you to plan a research protocol aimed at selection of the best form of your compound for development and manufacture.
The pharmaceutical industry is frequently confronted with the phenomenon of multiple crystal polymorphs of the same chemical entity. (Fig 1) The presence of multiple polymorphs of the active pharmaceutical ingredient is particularly challenging with solid, oral dosage drug products [1,2]. Polymorphism is often characterized as the ability of a drug substance to exist as two or more crystalline phases that have different arrangements and /or conformations of the molecules in the crystal lattices [3]. 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, toxicology results and clinical trial results. Ultimately both safety and efficacy are impacted by properties that vary among different solid forms. Furthermore, 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[4]. 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. For this reason pharmaceutical manufacturers often select a drug substance polymorphic form that has the desirable characteristics that will aide in the manufacture of the drug product formulation. Hence, it becomes critical to have a robust crystallization process that consistently produces the desired polymorphic form of the bulk pharmaceutical active ingredient.
Figure 1: Prevalence of Polymorphism In Screens Conducted at SSCI:
N= 230 compounds screened
- 90% have multiple forms
- 48% have polymorphs
- 38% have hydrates
- 30% have solvates
From data collected by G. Patrick Stahly, Ph.D. SSCI COO and CSO
FDA has issued regulatory guidelines [5,6] that outline the specifications and supporting documentation needed for a new drug application (NDA) and contains several decision trees to guide their selection; and literature report[7,8] to highlight major considerations for monitoring and controlling drug substance polymorphs and describe a framework for regulatory decisions regarding drug substance “sameness” considering the role and impact of polymorphism in pharmaceutical solids.
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#: )
- Mechanical
- Grinding
- Slurry Sonication TM (US Patent Applied For)
- Cocrystal Screening
- Thermal Techniques
- Computational Pattern Matching and Analysis (Patent # )
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:
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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 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.
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, automated testing procedure to quickly identify the salts with optimum properties.
Amorphous 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 pharmaceutically acceptable guest molecules into a crystal lattice along with the API, changing the physical properties of the solid. SSCI's Cocrystal Screen 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 scientists have elaborated the classical techniques to make them exceptionally effective. In addition, SSCI has special approaches to finding crystalline forms of poorly crystalline materials, such as cocrystal formation and alternative crystallization methods.
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, 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 2).
Figure 2: Energy Temperature diagram of an enantiotropic System
We are experienced in the design of crystallization-based separation of individual enantiomers from racemic mixtures (resolution). Like polymorphs, solid forms attained by the racemic mixture and pure enantiomer of a given compound can be crystallographically distinct. Use of SSCI's solids analysis capabilities allows determination of these relationships. For example, XRPD can often be used to determine if a racemic mixture exists as a racemic compound or a conglomerate.
Resolution efficiencies may be predicted based on binary phase diagrams, which SSCI can construct from thermal or solubility data. For example, Figure 3 illustrates a hypothetical racemic mixture. The relationship reveals that crystallization will not yield optical purification unless the starting material contains at least an 85% excess of one enantiomer.
Figure 3. Hypothetical racemic mixture.
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.
For more information, Please contact us.
- Yu, L.; Reutzel, S. M.; Stephenson, G. Pharm. Sci. Technol. Today, 1(3), 118, 1998.
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Giron, D. Thermochim. Acta, 248, 1, 1995.
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H. G. Brittain (Ed.), P1-34 “Polymorphism in Pharmaceutical Solids”, Marcel Dekker, Inc., New York, 1999.
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S. R. Byrn, R. R. Pfeiffer and J. G. Stowell, “Solid-State Chemistry of Drugs”, 2nd Edition, Academic Press, 1999.
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“Center for Drug Evaluation and Research Guidance: Submitting Supporting Documentation in Drug Applications for the Manufacture of Drug Substances”, February 1987, may be found at
http://www.fda.gov/cder/guidance/drugsub.pdf.
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S. R. Byrn, R. R. Pfeiffer, M. Ganey, C. Hoiberg and G. Poochikian, “Pharmaceutical solids: a strategic approach to regulatory considerations”, Pharm. Res. 12, 945-954, 1995.
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