Accelerated Stability Tests
A series of tests using high temperatures and/or humidities over the course of several months. This data is used to estimate the expiration date of the drug product.
Activation Energy (Arrhenius Activation Energy)
A physicochemical quantity that represents the barrier for a chemical reaction.
Active Pharmaceutical Ingredient or API
This is the substance in a drug which is pharmaceutically active. Some medications may contain more than one active ingredient. The traditional word for the API is phamacon, which originally denoted a magical substance or drug.
Adjunct
A substance added to a drug formulation to improve its pharmaceutical performance.
ADME
Absorption, distribution, metabolism and elimination (ADME) studies are conducted throughout the drug discovery process with the goal of reducing the attrition rate of these potential drug candidates as they progress through development.
- Absorption is the process of a substance entering the body.
- Distribution is the dispersion or dissemination of substances throughout the fluids and tissues of the body.
- Metabolism is the irreversible transformation of parent compounds into daughter metabolites.
- Excretion is the elimination of the substances from the body. In rare cases, some drugs irreversibly accumulate in a tissue in the body.
Amorphous Form
A solid that does not give a distinctive powder X-ray diffraction pattern. Amorphous solids are usually considered noncrystalline materials (ie glasses).
Amorphous Solid Dispersion
Amorphous Solid Dispersion(ASDs) offers the advantages of improved dissolution rates and higher apparent solubility characteristics of amorphous drug compounds.
Analytical Chemistry
Analytical chemistry is the study of the chemical composition of natural and artificial materials. Unlike other major sub disciplines of chemistry such as inorganic chemistry and organic chemistry, analytical chemistry is not restricted to any particular type of chemical compound or reaction. Properties studied in analytical chemistry include geometric features such as molecular morphologies and distributions of species, as well as features such as composition and species identity.
Angle of Incidence
The angle at which X-rays strike a plane in the crystal.
Anhydrate
A crystal form that contains no solvent of crystallization.
Anistropic Behavior
A term used to describe cases where a solid state reaction proceeds through different directions of the crystal at different rates; also referring to any observed property that varies in different directions in or on a crystal.
Atomic Displacement Parameter
A measure of the mobility or disorder of a given atom in a crystal structure, formerly called the temperature factor.
Automated Difractometer
See Diffractometer.
Avrami-Erofe’ev Equation
The equation that treats a solid-state reaction as a process controlled by random
nuclei growing in three dimensions and ingesting other nuclei. The equation is:
[–ln(l – ?)]n = kt where ? is the fraction reacted, n and k are constants, and t is time.
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Ball Mill
A relatively high-energy mill consisting of one or more balls in a chamber and used to reduce the particle size of solids. In the process, the ball mill may induce undesired solid-solid reactions or create amorphous material.
BET (Brunauer–Emmet–Teller) Adsorption Isotherm
A curve (usually sigmoidal) that describes the manner in which a substance absorbs a monolayer of an inert gas (usually nitrogen or krypton) at reduced temperatures.
Biaxial Crystal
Crystals in which the propagation of light differs in two directions. These crystals are of the triclinic, monoclinic, and orthorhombic systems.
Bioanalysis
Bioanalysis involves quantitative measurement of an active drug and/or its metabolites in biological matrices (plasma, brain tissue, urine etc.).
Bioavailability
Bioavailability refers to the difference between the amount of a drug to which a person is exposed and the actual dose of the substance the body receives. Bioavailability accounts for the difference between exposure and dose. A drug's therapeutic action is determined by the dose received at the target site in the body.
The fraction of an administered dose of unchanged drug that reaches the systemic circulation. When a medication is administered intravenously its bioavailability is 100%, however, when a medication is administered via other routes (such as orally), its bioavailability decreases, due to absorption, metabolism etc.
A term used to describe the biological availability of a drug. The bioavailability depends on the absorption, distribution, metabolism, and excretion of the drug. For example, the absorption of the drug depends on the dissolution profile of the dosage form, hence, the importance of dissolution testing in assuring consistent bioavailability.
Biobatch
Manufactured batch of a drug preparation that is used to test for biological response.
Birefringence
An optical property of all anisotropic crystals (ie virtually all drugs) observed as light and dark areas while the sample is rotated on the microscope stage of a polarizing microscope.
Bloch-decay Experiment
A solid-state NMR experiment where a single pulse on the observed nucleus is followed immediately by acquisition with high-power proton decoupling and usually magic-angle spinning. This technique accentuates highly mobile carbon nuclei.
Body-centered Space Group
A crystallographic space group containing a body-centered lattice, a lattice that contains a site in the center of the unit cell. A crystallographic space group containing a lattice point in the center of the unit cell symbolized by I.
Bragg Equation
The equation that relates the scattering of X rays from a crystal to the d-spacing between planes: n? = 2d sin?
Bulk Density
The mass of powder in a unit volume. Note this is not the true density of the substance, which is the mass per unit volume in a single crystal.
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Capping
A failure of tablets evidenced by the loss of layers of the tablet during routine handling.
Catemer
A network extending throughout a system; a type of hydrogen bonding arrangement consisting of an infinite chain.
cGMP (current Good Manufacturing Process) or GMP (Good Manufacturing Process)
Good Manufacturing Practice or GMP is a term that is recognized worldwide for the control and management of manufacturing and quality control testing of pharmaceutical products.
Chiral Compound
A compound that contains at least one asymmetric atom and is optically active.
Chirality
An object or a system is called chiral if it differs from its mirror image, and its mirror image cannot be superposed on the original object. For example a molecule may look identical but may react in a different way depending on how it is administered.
Clinical Trials
Clinical trials are conducted to allow safety and efficacy data to be collected for new drugs or devices. These trials can only take place once satisfactory information has been gathered on the quality of the product and its non-clinical safety.
Close-packing Theory
A theory of crystal packing advanced by Kitaigorodskii that states a crystal will contain the closest possible packing of molecules.
Cocrystal
A mixed crystal or crystal that contains two different molecules.
Cold Chain Distribution
This is distribution via a temperature controlled supply chain. One common temperature range for a cold chain in pharmaceutical industries is 2 to 8 °C. but the specific temperature (and time at temperature) tolerances depend on the actual product being shipped. This is important in the supply of vaccines to distant clinics in hot climates served by poorly developed transport networks.
Color Dimorphism
The existence of two crystalline forms of the same compound in which each exists as a different color.
Configurational Polymorphism
A type of polymorphism in which one labile isomer of a compound (eg a keto form) is present in one polymorph and another labile isomer (eg a enol form) is present in the other polymorph.
Contact Time
A solid-state NMR term referring to the length of the spin-lock period in which the Larmor frequencies of the proton and carbon are matched.
Contracting Area (disc, cylinder, or rectangle) Equation
A kinetics equation used to fit solid-state Kinetic data to a two-dimensional advancement of a phase boundary from the outer edges inward across the surface of the solid.
Coulter Method
A technique for determination of particle size distribution in which suspended particles pass through an orifice while changes in the resistance at the gap are recorded.
Cross Polarization
A technique which provides enhancement of nuclei with a low magneticgyro ratio (?) by transferring proton magnetization to the observed nucleus via matched spin-locking (Hartmann–Hahn) conditions at both frequencies. Since the sensitivity enhancement occurs on each scan (according to the ratios of the ? values) the experiment can be repeated much faster because of the faster relaxation of the higher ? nuclei.
Crystal
An orderly, infinite arrangement of molecules or atoms in a solid.
Crystal Form
A general term used to refer to the various types of crystalline solids of the same compound that can be obtained (ie polymorphs and pseudopolymorphs);
synonymous with crystal modification.
Crystal Habit
Crystals with the same internal structure but different external shape, thus, crystal in which different faces have developed during growth; synonymous with morphology.
Crystal Lattice
The three-dimensional molecular repetition of the motif within a crystal.
Crystal Packing
The arrangement of molecules in a crystal and the contacts between these molecules.
Crystal Ripening
The process of reaching equilibrium after a crystallization is largely complete by
continued stirring. This may bring about changes in crystal size, shape and
perfection as high energy sites are driven to equilibrium.
Crystal Structure
The internal arrangement of atoms (and thus molecules) in a solid. The crystal structure is determined by X-ray crystallographic techniques and includes information about intramolecular and intermolecular contacts.
Crystal System
The space group and crystal lattice to which a crystal structure belongs.
Crystalline Form
A solid form that is crystalline; a solid form that gives a diffraction pattern. This includes polymorphs, solvates, hydrates, and desolvated solvates.
Crystallinity
The ratio of crystalline and amorphous components in a sample. High crystallinity connotes a low amorphous component.
Cube-root Kinetics
A diminishing sphere kinetics model with regard to particles of radius r: r(1 – ?)3 = kt where r is the particle radius, ? is the fraction reacted, k is a constant, and t is time.
Cube Crystal Class
A crystal class containing four three-fold rotation axis, one along each unit cell diagonal. This class contains 36 space groups and has two restrictions: 1) the lengths of all axes are equal, and 2) all angles are equal to 90°.
Cycloaddition Reaction
A chemical reaction that involves the addition of two substrates to form a ring
system (eg the solid-state photodimerization of cinnamic acids). Cycloaddition reactions are controlled by The Woodward–Hoffmann rules.
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Decarboxylation Reaction
A chemical reaction that involves the loss of CO2 from a solid (eg the decarboxylation of 4 aminosalicylic acid).
Defects
Sites of imperfection in the crystal packing of solids. The most common defects are screw dislocations, slip dislocations, and orientational defects.
Dehydration Reaction
A reaction that involves loss of water from the crystal. The loss may be due to the physical loss of water from the crystal lattice or through a chemical reaction.
Dehydrogenation Reaction
A reaction that involves loss of hydrogen gas.
Deliquescence
The uptake of atmospheric moisture by a solid, sometimes ending in spontaneous liquefaction of the solid.
Density Rule
The rule states that if a polymorph has a lower density than another polymorph at room temperature, then it may be assumed that at absolute zero the form with the lower density is metastable.
Desolvated Solvate
A crystalline solvate that has lost the solvent of crystallization but has largely retained the original crystalline lattice.
Desolvation
A reaction in which the solvent of crystallization is lost from a crystal. Desolvation can be accompanied by a polymorphic transformation, or the original crystal structure can be maintained to produce a desolvated crystal.
Differential Scanning Calorimetry (DSC)
An analytical technique measuring the heat Flux (the quantity of heat transmitted per unit time) of the sample during a controlled heating process.
Differential Thermal Analysis (DTA)
An analytical technique in which the difference in temperature between the
sample and an inert reference is detected during a controlled heating process.
Diffraction Pattern
The recorded form of diffraction peaks and their relative intensities obtained when a material is subjected to X-ray diffraction analysis. The pattern may be in the form of a chart tracing or as bands on photographic film.
Diffractometer
A device used to accurately measure the intensities of diffracted X-rays as a function of the incident angle of the X-ray beam. This unit is usually computer controlled and measures the intensities using a counter.
Dimerization
A chemical reaction in which two monomers combine to form a single molecule.
Dipole Moment
A vector indicating the magnitude and direction of the uneven charge distribution in a covalent bond or molecule. The vector is represented by the symbol µ with units of debyes, abbreviated D.
Direct Methods
A group of statistical methods used to determine a crystal structure based on analysis of diffracted intensities.
Discovery Pharmacology
In pharmacology, drug discovery is the process by which drugs are discovered and/or designed.
Dissolution Profile
A multi-time point description of the dissolution of a dose under standardized conditions.
Dissolution Rate
The rate of dissolution of a solid, usually measured in water at physiological pH and temperature. An important physicochemical quantity used to predict the bioavailability of drugs.
Drug Development
Drug Development (or preclinical development) is the process of taking a new chemical lead through the stages necessary to allow it to be tested in human clinical trials.
Drug Metabolism
Drug metabolism is the metabolism of drugs, their biochemical modification or degradation, usually through specialized enzymatic systems. Drug metabolism often converts lipophilic chemical compounds into more readily excreted polar products. Its rate is an important determinant of the duration and intensity of the pharmacological action of drugs.
Dynamic Mode
A common thermogravimetric analysis technique in which the temperature is raised at a known rate, typically linear.
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Efficacy
The ability to produce the desired amount of effect.
The ability of a drug to induce a biological response in its molecular target.
E Ray
See Extraordinary ray.
Efflorsescence
The loss of gas from a solid or liquid.
Electron-density Map
A plot of electron density versus location in a unit cell. Electron-density maps are used early in a crystal structure solution to solve the structure.
Electron-spin Resonance (ESR) Spectroscopy
A method involving measuring the resonance of free electrons in material. This method can provide structural and dynamic information about a solid.
Electrophilic Aromatic Substitution Reaction
A common chemical reaction that involves the attack of the ? electrons of an aromatic ring on an electrophile to form a resonance-stabilized carbocation intermediate that then looses a proton to form a substituted aromatic compound.
Enantiomer
In a chiral compound, either of the two molecular species, R and S, having equal optical rotation but of opposite sign and in which the mirror image is not superimposable with the original structure.
Enantiotropy
Referring to a situation in which the rank order of stability of the various solid forms changes at different temperatures (in contrast to monotropic).
Enthalpic Change
A change in the heat (?H) of the compound. For example, a change in the crystal form or structure is an enthalpic change.
Enthalpy of Fusion Rule
If the higher melting form has the lower enthalpy (heat) of fusion the two modifications are enantiotropic. If the lower melting form has the lower entropy (heat) of fusion the two modifications are monotropic.
Enthalpy of Transition Rule
This rule states that if an endothermic transition is observed at some temperature it may be assumed that there is a transition point below it and that the two forms are related enantiotropically. If an exothermic transition is observed at some temperature it may be assumed that there is no transition point below it and that the two forms are either related monotropically or the transition temperature is higher.
Ε
The refractive index of the extraordinary ray having the maximum value.
Ε
The refractive index of the extraordinary ray that is between the maximum and minimum index values.
Excimer
An excited-state complex formed by two or more molecules.
Excipient
Additives used in the preparation of the dosage form to either improve the handling and manufacturing of a product or to act as a filler (ie lactose, cellulose, starch, or dicalcium phosphate).
Expiration Date
The date appearing on the label of a drug after which it should not be used or sold.
Extraordinary Ray
The component of plane-polarized light that travels through a uniaxial crystal at a direction-dependent velocity.
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Face
Any one of the outer plane surfaces of a crystal or geometric solid.
Face-centered Space Group
A crystallographic space group containing a pair of lattice points on opposite faces (symbolized by A, B, or C if the bc, ac, or ab faces are centered or F is all faces are centered).
Fast-to-IND
Fast-to-IND reduces time from API to IND (Investigational New Drug - see below) submission to 25 weeks or less for appropriate compounds. These reductions are achieved by merging traditional preformulation, drug substance, drug product, clinical supplies and analytical method development silos into a single unit managed by a veteran, dedicated project manager and staffed by professionals with experience spanning the development process.
Filterability
Ability to filter a solid; related to particle size and morphology of the solid.
Flowability
A measure of the freedom with which a powder flows through tubes and orifices such as those encountered in unit operations.
Formulation
Studies leading to the choice of specific processes and additives to be used in the final preparation of a drug dosage form. Also, the composition of that preparation.
Fourier Transform (FT)
The mathematical treatment of data in which an ensemble of sinusoidal signals are deconvoluted into individually contributing frequencies, amplitudes, and phases.
Fraunhofer Diffraction
A laser-light scattering in which particles create radially symmetrical diffraction patterns consisting of a bright center and coaxial light and dark rings. The angle of diffraction is size dependent; smaller particles diffract at larger angles compared to larger particles. Also known as static-light scattering (SLS) or low angle forward light scattering.
Free-radical Reaction
A chemical reaction that conceptually involves three sequential types of reactions: 1) initiation steps in which free radicals (eg R• or Cl•) are formed, 2) propagation steps in which the free radicals react with molecules to form products and other free radicals, and 3) termination steps in which free radicals combine to form molecules.
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Gas Chromatography
A chromatographic technique in which the sample is volatilized and passed through a column to separate the components of a sample. The column is packed either with a polymeric stationary phase coated on a solid support or simply a thin layer of polymer on the inner surface of a capillary.
Glass
A solid that does not have an ordered arrangement of molecules and is hard or brittle; an amorphous solid below its glass-transition temperature.
Glass Transition Temperature
The temperature above which a glassy amorphous solid becomes rubbery, Tg.
Glassy State
A state of an amorphous material having rather low mobility, as in window glass.
Glide Plane
A symmetry element involving reflection through a plane followed by a translation.
GLP
Good Laboratory Practice.
Goniometer Head
A device used to mount crystals and control their orientation at precise angles.
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Habit
See Crystal habit.
Hammett Equation
A linear free-energy relationship for substituent effects in reactions or ionizations (pKa) given as:? log = ?X? or –?GX = ?X?2.3RT – ?GH where kH is the rate constant or equilibrium constant for the parent compound, kX is the constant for the compound bearing a substituent X, ? is a constant for a given reaction under a given set of conditions, and ?X is a constant characteristic of the group X.
Hartman–Hann Condition
A spin-lock experiment that increases the efficiency of cross polarization; it uses two rf fields, one at the Larmor frequency of the protons and one at the Larmor frequency of the carbons.
Heat Capacity Rule
This rule states that at a given temperature, if the higher melting polymorph has a heat capacity greater than another modification, the system is enantiotropic. Otherwise, the system is monotropic.
Heat Conduction Calorimetry
A technique in which the response of the instrument is directly proportional to the rate of the heat produced in the sample cell. Theadvantage of this technique is that small values of heat (µW) can be detected.
Heat of Fusion Rule
See Enthalpy of fusion rule.
Heat of Transition Rule
See Enthalpy of transition rule.
Heavy-atom Method
A method used to determine the crystal structure of compounds that contain atoms with atomic numbers greater than 17.
Helium Pycnometry
An analytical method for determining the density of a powdered solid. An accurately weighed sample (~5 g) is placed in a sample cell and evacuated to remove ambient gases. The cell is then pressurized with helium, followed by adiabatic expansion into a chamber of known volume. The resulting pressure is recorded after thermal equilibrium. The density of the solid is calculated as follows: VS = V1 – density = WS where WS is the weight of the sample, VS is the volume of the sample, V1 is the volume of the sample cell, V2 is the volume of the expansion chamber, P1 is the original pressure of the sample cell, and P2 is the pressure of the system after the expansion step.
Hexagonal Crystal Glass
A crystal class containing one six-fold rotation axis. This class contains 27 space
groups and has three restrictions: 1) the lengths of the a and b axes are equal, 2) the ? and ? angles are equal to 90°, and 3) the ? angle is equal to 120°.
High-performance Liquid Chromatography (HPLC)
A chromatographic technique that involves passing a solution at high pressures through a packed column of fine particles. The components of a sample are separated on the column and noted by a detector (eg UV-Vis, refractive index, potentiometric, etc.) An octadecylsilyl (C- 18) column is the most commonly used column and a UV detector is the most commonly used detector.
Hygroscopic Solid
A solid that can adsorb atmospheric moisture. There is both a kinetic and a thermodynamic component to this process. The kinetic component determines the rate of water uptake, while the thermodynamic component determines the energy of this process.
Hygroscopicity
The hygroscopic nature of a solid.
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Image Analysis
An automated microscopic technique for analyzing particle properties, especially shape and size distributions.
Independent Molecule
A term used to describe the unique, non-symmetry-related molecules in a unit cell.
Indicatrix
A structural representation, portrayed as an ellipsoid, of the magnitudes and directions of the O and E rays within a crystal.
Infrared Spectroscopy
A method of analysis that involves the absorption of infrared energy by the sample. The molecules that absorb the infrared energy are in an excited, vibrational state and the wavelengths of the various vibrations reveal structural details of the given molecules.
Interfacial Angle
The angle between faces in a crystal. This angle is dictated by the Miller indices of the faces and the crystallographic unit cell.
Intermolecular Contacts
Contacts between adjacent molecules in a crystal. These contacts define the crystal packing.
Interrupted Decoupling
A brief delay (20–50 µs) in the 1H–13C contact time during which the magnetization of the carbons directly attached to protons rapidly dephase, with the exception of methyl carbons. The result is an enhancement of nonprotonated carbons, methyl groups, and sometimes highly- mobile methylenes. Also known as NQS (non-quaternary suppression).
Intramolecular Contacts
Non-covalent contacts between atoms in the same molecule within a crystal.
Intrinsic Dissolution
A method of measuring dissolution that eliminates the effect of surface area.
Intrinsic Dissolution Rate (IDR)
The rate of dissolution measured in an intrinsic dissolution apparatus. The intrinsic dissolution rate is independent of surface area.
Investigational New Drug (IND)
The United States Food and Drug Administration's investigational new drug (IND) program is the means by which a pharmaceutical company obtains permission to ship an experimental drug across state lines (usually to clinical investigators) before a marketing application for the drug has been approved. The FDA reviews the IND application for safety to assure that research subjects will not be subjected to unreasonable risk. If the application is approved, the candidate drug usually enters a Phase 1 clinical trial.
In Vitro
The technique of performing a given experiment in a controlled environment outside of a living organism, for example in a test tube.
In Vivo
Refers to experimentation done in or on the living tissue of a whole, living organism.
ION Channel
An ION channel is a pore-forming protein which helps to establish and control the small voltage gradient across the plasma membrane of all living cells.
Ionic Bond
A bond in which the predominant forces are ionic in nature.
Ionic Crystal
A crystal composed of ions in which each ion of a given charge is equidistant from a small number of ions of opposite charge (eg sodium chloride).
Isomorphous Replacement Method
A method of determining crystal structure used for proteins. This method involves replacing heavy atoms in a crystal with different heavy atoms.
Isothermal Mode
A thermogravimetric analysis technique in which the temperature of the sample is held constant.
Isotropic
Having identical properties in all directions.
IVRS
Interactive Voice Response Systems use the telephone as a means of inputting data.
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Jander Equation
A simplified version of the three-dimensional diffusion kinetic equation.
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Larmor Frequency
The frequency of precession of a nucleus in a magnetic field.
Laser Light Scattering
Various particle-size distribution analyses that examine the optical response of a suspended powder to illumination by a laser (cf. Fraunhofer diffraction, time-domain and image analysis.
Law of Rational Indices
A rule stating that the major faces on a crystal will generally be related to the principle dimensions of the unit cell and will have Miller indices with low integer values [(100), (101), (210), etc.]
Loosening
See Molecular loosening.
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Magic Angle
The angle (54° 44') at which solid samples are often spun in solid-state NMR
spectroscopy. This spinning removes the effect of the random orientation of the
powdered solid with respect to the magnetic field.
Magic-angle Spinning
A solid-state NMR technique involving spinning the sample at an angle of 54°44’
to reduce the anisotropic chemical shifts in a solid.
Melt-back
A phenomena that occurs during Lyophilization (freeze drying) where the solid melts to form a crust.
Metabolites
are the intermediates and products of metabolism.
Metastable Form
A form other than the most stable form.
Microscopy
Examination of crystals on a microscope by various techniques. (??by convention) is not equal to 90°.
Miller Index
A set of three integers used to designate the lattice planes of the crystal. Miller indices are used to designate: a) a set of lattice planes [eg the (010) plane], b) a particular member of this set, or c) a face of a macroscopic crystal [eg the (010) face].
Mirror Plane
A crystallographic plane corresponding to a reflection operation (see Table 1.1).
Molecular Change
The second step of a hypothetical solid- state reaction. This step involves the actual chemical reaction that occurs. This step is similar to the corresponding reaction in solution.
Molecular Loosening
The first step of a hypothetical solid-state reaction. This step allows the reacting molecules to gain enough molecular freedom to react. For solid–gas reactions, this step also involves diffusion of gases to the reaction site.
Monoclinic Crystal Class
A crystal class containing one two-fold rotation axis along the b axis. This class consists of 13 space groups and has no restrictions on the lengths of the axes except that one angle
Monohydrate
A crystal form containing one mole of water per mole of compound.
Monotropic
Referring to a system in which various solid forms retain the rank order of their stabilities at all temperatures (in contrast to enantiotropic).
Morphology
The external shape of a crystal; synonymous with the crystal habit.
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Non-bonded Interaction
A through-space interaction of atoms that are typically electrostatic or van der Waals in nature.
Non-covalent Attractive Force
See Non-covalent interaction.
Non-covalent Attractive Interaction
See Non-covalent interaction.
Non-covalent Interactions
The van der Waals forces between multipoles in molecules that are responsible for many phenomena including cohesion of most solids, surface tension, friction, changes of phase, viscosity, the Joule-Thomson effect, and causing deviations in the ideal gas law.
Non-stoichiometric Hydrate (or solvate)
A solvated crystal structure in which the solvent molecules are not in well-defined positions and therefore are present in variable amounts, depending on the vapor pressure of the solvent in the system, (ie the relative humidity in the case of crystal hydrates).
NQS
See Interrupted decoupling
Nuclear Magnetic Resonance (NMR) Spectroscopy
An analytical method used to study both liquid and solid samples. It involves placing the sample in a magnetic field and measuring the energy differences between spin states of the nuclei (most commonly protons and carbons).
Nucleation
The formation of stable molecular assemblies leading to crystallization. Also, the initiation of a solid-state reaction. This occurs at a defect or impurity site in the crystal. The solid-state reaction often spreads from this site throughout the crystal.
Nucleation Site
The place at which nucleation occurs within a crystal.
Nuclei
Ordered arrays of solute molecules of sufficient size to persist in a given solution.
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O Ray
See Ordinary ray
Optical Axis
The direction in a crystal in which both components of the plane-polarized light are equal.
Optical Goniometry
See Reflective goniometry.
Ordinary Ray
The component of plane-polarized light that travels through a uniaxial crystal with a constant velocity.
Organic Crystal
A crystal consisting of a regular arrangement of organic molecules held together by van der Waals forces.
Orientational Defect
A defect at which the tenant molecule takes up an abnormal orientation.
Ortep Drawing
A structural representation of a set of atoms in which the atoms are portrayed as ellipsoids that depicts the atomic displacement parameters for those atoms. These representations were originally drawn using the ORTEP program.
Orthorhombic Crystal Class
A crystal class containing three mutually perpendicular two-fold rotation axes. This class consists of 59 space groups and has one restriction: all of the angles are equal to 90°. There are no restirictions on the lengths of the axes.
Ostwald Ripening
A spontaneous process during which ultrafine (high-energy) crystals dissolve and the corresponding material redeposits on larger crystals.
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Packing
See Crystal packing.
Particle-size Distribution
The size distribution of particles in a solid, typically represented graphically as a histogram or numerically as three values: 1) 10% of the sample is less than the value stated, 2) 50% of the sample is less than the value stated (the median), and 3) 90% of the sample is less than the value stated.
Pathology
The study and diagnosis of disease through examination of organs, tissues, bodily fluids and whole bodies.
Pharmaceutical Sciences
The pharmaceutical sciences are a group of interdisciplinary areas of study involved with the design, action, delivery, disposition, and use of drugs. This field draws on many areas of the basic and applied sciences, such as chemistry (organic, inorganic, physical, biochemistry and analytical), biology (anatomy and physiology, biochemistry, cell biology, and molecular biology), mathematics, physics, and chemical engineering, and applies their principles to the study of drugs.
Pharmaceutics
Pharmaceutics is the discipline of pharmacy that deals with all facets of the process of turning a new chemical entity (NCE) into a medication able to be safely and effectively used by patients in the community. Pharmaceutics is the science of dosage form design. There are many chemicals with known pharmacological properties but a raw chemical is of no use to a patient. Pharmaceutics deals with the formulation of a pure drug substance into a dosage form such as a tablet or capsule.
Pharmacodynamics
Pharmacodynamics is the study of the biochemical and physiological effects of drugs on the body or on microorganisms or parasites within or on the body and the mechanisms of drug action and the relationship between drug concentration and effect.
Pharmacodynamic studies the actions of drugs within the body. This includes the routes and mechanisms of absorption and excretion, the rate at which a drug action begins and the duration of the effect on the body.
Pharmacokinetics
Pharmacokinetics (in Greek: “pharmacon” meaning drug and “kinetikos” meaning putting in motion, the study of time dependency; sometimes abbreviated as “PK”) is a branch of pharmacology dedicated to the determination of the fate of substances administered externally to a living organism. Pharmacokinetics is often studied in conjunction with pharmacodynamics.
Pharmacokinetics is a branch of pharmacology dedicated to the determination of the fate of substances administered externally to a living organism. It explores what the body does to the drug.
Phase Problem
Although the amplitude F(hkl) of the diffracted beam is readily available, the phase ?(hkl) necessary to compute the electron density is not known because X- rays cannot be focused. The phase is needed to determine the three-dimensional arrangement of the atoms without which the stereochemistry cannot be determined.
Phase Transformation
A transformation of one crystalline form of a solid to another. This can be a solid- solid, a solid-liquid-solid, or a vapor-mediated transformation.
Photochromism
A compound exhibits photochromism if, upon exposure to light, a color change occurs. Often the color change is reversible.
Photomicrography
The technique of photographing a crystal on a microscope, sometimes at various stages in a reaction.
Physical Chemistry
Physical chemistry is the application of physics to macroscopic, microscopic, atomic, subatomic, and particulate phenomena in chemical systems within the field of chemistry traditionally using the principles, practices and concepts of thermodynamics, quantum chemistry, statistical mechanics and kinetics.
Physical Stability
A term used to refer to the stability of a drug with respect to physical transformations, for example, to another polymorph or crystal form.
Physical Transformation
A transformation of a solid in which the crystal structure or content of the crystal changes but in which no covalent bonds are made or broken. Physical transformations include polymorph transformations and desolvations.
Plane-polarized Light
The result of light passing through a polarizing filter resulting in only the extraordinary ray emerging as light polarized in only one plane.
Pleochroic
Showing more than one color.
PLS (partial least-squares) Treatment
A technique used to perform quantitative analyses on multicomponent mixtures with overlapping bands. PLS also allows calibration using mixtures permitting the modeling of interactions between components and the use of combinations of multiple numbers of wavelengths in the calibration.
Polarizability
The ability to be polarized.
Polarography
An analytical technique that measures the current flow at a liquid-drop electrode at a given potential. The current flow is proportional to the amount of compound present.
Polychromism
The capcity of a solid to exhibit more than one color.
Polymorph (polymorphism)
One of the different crystal structures in which a compound can crystallize. Polymorphs are best characterized by their space group and unit-cell parameters. This term is usually reserved for materials with the same elemental analysis.
Polymorphic Transformation
A physical transformation in which the crystal structure of a compound is converted to a different crystal structure.
Polymorphism
Polymorphism in biophysics is the aspect of the behaviour of lipids that influences their long-range order, i.e. how they aggregate. This can be in the form of spheres of lipid molecules (micelles), pairs of layers that face one another (lamellar phase, observed in biological system as a lipid bilayer), a tubular arrangement (hexagonal), or various cubic phases (Fd3m, Im3m, Ia3m, Pn3m, and Pm3m being those discovered so far
Polymorph Screening
Pharmaceutical molecules are notorious for forming polymorphs if crystallized and extensive polymorph screening studies are typically performed before selecting an optimum form for further development.
Potent Compound
A Potent Compound is defined as a pharmacologically active ingredient or intermediate with biological activity at 150 ug/kg of body weight or below in adults (therapeutic dose at or below 10 milligrams); an active pharmaceutical ingredient or intermediate with an occupational exposure limit (OEL) at or below 10 ug/m^3 of air as an 8-hour time weighted average; a pharmacologically active ingredient or intermediate with high selectivity (i.e. ability to bind to specific receptors or inhibit specific enzymes) and/or the potential to cause cancer, mutations, developmental effects, or reproductive toxicity at low doses (at or near the therapeutic dose or lower); or a novel compound of unknown potency and toxicity."
Powder Bridging
The formation in a bulk powder of large cohesive regions, or “bridges,” that interfere with uniform flow of the powder in pharmaceutical operations.
Powder Diffraction Method
See X-Ray powder diffraction.
Precession Camera
A camera used in X-ray crystallography in which the center of a flat film is always kept aligned with the direct beam of X-rays as a crystal is oscillated.
Precession Photograph
An X-ray diffraction photograph made on a precession camera. Direct measurement of all lattice parameters are possible from a series of these photographs.
Preclinical Studies
Pre-clinical studies involve in vitro (ie test tube or laboratory) studies and trials on animal populations Wide-ranging dosages of the study drug are given to the animal subjects to assist pharmaceutical companies in deciding whether it is worthwhile to go ahead with further testing.
The main goals of pre-clinical studies (also named preclinical studies and nonclinical studies) are to determine a drug's pharmacodynamics (PD), pharmacokinetics (PK), ADME, and toxicity through animal testing. This data allows researchers to estimate a safe starting dose of the drug for clinical trials in humans.
Preferred Orientation
The crystals in a powder are said to be in a preferred orientation when they are not randomly oriented and their diffraction intensities differ from those obtained when crystals are randomly oriented.
Primary Nucleation
Nucleation in a system that does not contain crystalline matter.
Primary Packaging
Primary packaging is the material that first envelops the product and holds it.
Primitive Space Group
A space group that contains only a single lattice point or a single unit of the repeated motif in a crystal lattice; symbolized by P (or R for rhombohedral crystals).
50% Probability Level
Probability A scale factor used for Ortep representations in which the instantaneous position of the atomic center will be within the ellipsoid 50% of the time.
Prout
Tompkins kinetics—The equation that treats a solid-state reaction as a process controlled by growing nuclei that branch into chains. The equation is: = kt where ? is the extent of reaction, k is the rate constant, and t is the time
Pseudopolymorph
A polymorph that differs from a true polymorph by the incorporation of solvent.
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Quasi-isothermal Mode
A thermogravimetric analytical technique in which the sample is heated at a fixed temperature to a constant mass and the process repeated stepwise at increasingly higher temperatures.
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Reaction Cavity
A hypothetical volume wherein significant molecular motion, hence reaction, can take place within a solid.
Reaction Order
The sum of the exponent of the reactants in the kinetics equation for a given reaction.
Rearrangement Reaction
A chemical reaction in which covalent bonds are made and broken, but in which the molecular formula remains the same.
Reflected Light
Used to observe gross properties of particles (cf., transmitted light).
Reflective Goniometry
A technique by which the interfacial angles of a single crystal can be determined.
Refractive Index
The ratios of the velocities of light in a medium and in air under the same conditions. Measured by the ratio of the sines of the angles of incidence and refraction.
Rhombohedral Crystal Class
A subclass of the trigonal crystal class containing a three-fold rotation axis along a diagonal of the unit cell. This class contains 7 space groups and has two restrictions: 1) the lengths of the three axes are equal, and 2) the three angles are equal, but need not equal 90.
Rietveld Method
A computational treatment of diffraction data that creates an effective separation of the overlapping data in a typical powder X-ray diffraction pattern, thereby often allowing an accurate determination of the structure without the need of single-crystal data.
Rotation Axis
A symmetry element involving an n-fold rotation about an axis.
Rotatory-inversion Axis
A symmetry element involving an n-fold rotation followed by an inversion. Also called a center of symmetry.
Rubber
An amorphous material somewhat above its glass transition temperature and having a rubbery consistency.
Rubbery State
The state of an amorphous material at a temperature above its glass transition temperature and below the temperature of liquefaction.
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Safety Pharmacology
Studies which investigate the potential undesirable pharmacodynamic effects of a substance on the functions in relation to the exposure in the therapeutic range and above.
Salt Screening
Salt screening searches and identifies salts which may be more attractive development candidates compared to the free form. Salt screening can identify a new salt for the API which has the potential to facilitate and speed up the development of the compound.
Saturation
The concentration of a solution in which a solute is at its equilibrium solubility in the respective solvent.
Scanning Electron Microscopy (SEM)
A microscope in which a focused beam of electrons is directed on a sample to produce several interactions of which secondary electrons and backscattered electrons are the basis of the image. Resolution is typically 100 Å and has a large depth of field.
Screw Axis
A symmetry element involving an n-fold rotation followed by translation parallel to the axis of rotation. It may be visualized as a screw.
Screw Dislocation
A defect in a crystal having a screw-type appearance as observed with an electron microscope or atomic force microscope.
Secondary Nucleation
The occurance of crystal nuclei brought about by operations such as stirring and impact after the system has undergone primary nucleation.
Secondary Packaging
Secondary packaging is outside the primary packaging and can be used to group primary packages together.
Seeding
The addition of solid particles, usually of the desired phase, to a crystallization process in order to induce crystal nucleation under controlled conditions.
Semimicro Hygrostat
A small chamber in which a sample is suspended over a saturated-salt solution that provides a determined relative humidity. The chamber can be disassembled with a minimum of exposure of the sample to the atmosphere while weighing to determine the increase or decrease in mass of the sample.
Sesquihydrate
A crystal form containing one and one-half moles of water per mole of compound.
Single Crystal
A crystal consisting of a non-interrupted repetition of the unit cell in three dimensions. The structure of a single crystal can be determined by single-crystal X-ray diffraction.
Singlet Oxygen
An oxygen atom in its singlet excited state. Singlet oxygen usually gives products resulting from cycloaddition.
Singlet-oxygen Sensitizer
An organic compound (e.g., the dye rose bengal) that converts triplet oxygen to singlet oxygen by transfer of energy.
Sink Condition
Conditions during a dissolution or solubility experiment where the concentration in solution is much less than the solubility.
Size Distribution
See particle-size distribution.
Slip Dislocation
A type of defect in which the crystal planes have slipped relative to each other. A slip dislocation can bring molecules into intermolecular interactions that are not found in the bulk crystal.
Solid Form
A general term used to describe polymorphs, pseudopolymorphs, or amorphous forms; synonymous with solid modification.
Solid Solution
The random distribution of one solid in another.
Solid-gas Reaction
A reaction of a solid with a gas (e.g., the reaction of acid crystals with ammonia) or a reaction producing a gas and a solid as products (e.g., decarboxylation reactions).
Solid-solid Reactions
Reactions between two solids without the involvement of a solvent, generally involvind four steps: 1) loosening of the molecules at the reaction site, 2) molecular change, 3) solid solution formation, and 4) separation of the product phase.
Solid State Chemistry
Solid state chemistry is the study of the synthesis, structure, and physical properties of solid materials.
Solid-state Hydrolysis
A solid-state reaction in which water hydrolyzes a compound (eg hydrolysis of acetylsalicylic acid to form acetic acid and salicylic acid).
Solid-state Oxidation Reactions
A class of solid-gas reactions involving the reaction of a solid with oxygen.
Solid-state Photochemical Reactions
Reactions that proceed by absorption of light by the molecule and subsequent bond
formation or breakage. The products of these reactions differ from those in solution. Solid-state reactions that are heat induced. Solid-state rearrangement reactions are important members of this class.
Solid-state Thermal Reactions
Solid-state reactions that are heat induced. solid-state rearrangement reactions are important members of this class.
Solubility
The amount of solute dissolved in a unit volume of a solvent at equilibrium at a given temperature and pressure. Each form of a substance has a characteristic solubility.
Solvate
A crystal form that contains either stoichiometric or nonstoichiometric amounts of solvent.
Space Group
One of 230 possible three-dimensional arrangements of molecules in a crystal. A listing of all of the space groups can be found in International Tables for Crystallography, Volume 1.
Specific Surface Area
The characterization of a powder by determining the surface area per unit weight.
Spin Locked
A technique in NMR in which the magnetization is locked along the y axis by the rf field. A means of effectively preventing chemical shift evolution by using a high-power rf field during an NMR experiment.
Stability
A term used to describe the resistance of a solid drug or solution of a drug to reaction.
Stable Form
The solid form of a substance having the highest thermodynamic stability (eg lowest solubility) among all the forms that might be encountered under the given conditions.
Static-light Scatering (SLS)
See Fraunhofer diffraction.
Stereoscopic Packing Drawing
A three-dimensional representation of a crystalline arrangement of molecules using side-by-side views at slightly different angles. These representation may be viewed unaided or by using special viewers.
Structure Factor
The intensity and phase of a diffracted X-ray by a unit cell denoted by F or F(hkl).
Sublimation
A change in state from a solid to a gas and then back to a solid. Sublimation can be used to purify a solid and also may be involved in solid-state reactions and phase transformations.
Supersaturation
A solution that contains a concentration of solute greater than the equilibrium solubility value.
Suspension
A liquid that contains undissolved solid distributed evenly throughout the mixture.
Symmetry Element
The various formal spatial relationships that govern the orderly three-dimensional propagation of an object in space (ie in crystal growth, the molecules of the compound). (See Table 1.1).
Symmetry Operation
An operation that returns the contents of the unit cell unchanged. Symmetry operations include n-fold rotations, rotary inversions, point inversions, mirror planes, glide planes, and screw axes.
Syringeability
The ability of a suspension to pass readily through a syringe and needle. For example, long needle-like crystals in suspension may have poor suspension syringeability.
Systematic Absence
The absence of certain hkl reflections in the X-ray diffraction of a single crystal. Systematic absences are used to determine the space group and symmetry of a crystal.
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Tableting Behavior
A general term for behavior of crystals upon compression into tablets.
Temperature Factor (thermal factor)
See Atomic displacement parameter.
Tetragonal Crystal Class
A crystal class containing a four-fold rotation axis or rotatory-inversion axis along c. This class contains 68 space groups and has to restrictions: 1) the lengths of the a and b axes are identical, and 2) all angles are equal to 90°.
Tg
See Glass-transition temperature.
Thermal Analysis
One of a group of methods used to characterize solids, thermogravimetric analysis, differential thermal analysis, differential scanning calorimetry.
Thermochromism
A compound is thermochromic if, upon exposure to heat, a color change occurs. Often this color change is reversible.
Thermogravimetric Analysis (TGA)
An analytical technique in which the weight change of the sample is measured during heating.
Thermomicroscopy
A technique that involves observation of crystals on a microscope during heating.
Thin-layer Chromatography (TLC)
A chromatographic method of separating compounds eluted with a solvent after applying them to a thin layer of adsorbent adhered to a solid support (eg glass, plastic, or aluminum).
Threshold Temperature
The temperature at which an arbitrarily defined 2% of the solvent of crystallization is lost from a solvate. It is conveniently measured by TGA using a 6 °C/min heating rate.
Time-domain Analysis
A technique used to determine the size of a particle (0.5–3600 µm in diameter) by measuring the time required for a laser beam moving at a fixed velocity to cross a particle.
Topochemical
The term used to describe the control of solid-state reactions by selective crystal packing. A reaction is topochemical if the structure of the products can be explained by the crystal packing of the reactant crystal.
Topochemical Postulate
This postulate states that, because a solid-state reaction may occur within the solid or at the surface of the solid, the outcome of the reaction is for the most part determined by the spatial relationships of the reactants.
Topotactic
See Topotaxy.
Topotactic Reaction
A reaction exhibiting topotaxy.
Topotaxy
A term used to describe a solid-state reaction whose products have a preferred orientation relative to a crystallographic direction of the parent crystal.
Toxicology
Toxicology (from the Greek words toxicos and logos) is the study of the adverse effects of chemicals on living organisms. It is the study of symptoms, mechanisms, treatments and detection of poisoning, especially the poisoning of people.
Transmitted Light
Used to examine single crystals and their optical properties. (cf. reflected light).
Triclinic Crystal Class
A crystal class of containing either no symmetry or a rotatory-inversion axis in any direction. This class contains 2 space groups and has no restrictions on the lengths of the axes or the values of the angles.
Trigonal Crystal Class
A crystal class containing a three-fold rotation axis along the diagonal of the unit cell. This class is divided into two subclasses. One subclass, designated with hexagonal axes, contains 18 space groups and has three restrictions: 1) the lengths of the a and b axes are identical, 2) the ? and ? angles are equal to 90°, and 3) ? is equal to 120°. For a description of the other subclass, see Rhombohedral crystal class.
Trituration
A process involving grinding a solid with a liquid.
Twofold Rotation Axis
A symmetry axis in which a rotation of 180° produces no change.
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Ultraviolet Spectroscopy
An analytical spectroscopic technique used to study the electronic excitation of a substance. Application of this technique usually requires dissolution of the sample.
Undersaturation
The condition when solution concentration is less than the saturation value (ie when solute concentration is less than its solubility in the respective solvent).
Uniaxial Crystal
An anisotropic crystal in which the velocities of both plane-polarized light components traveling through the crystal are equal; a crystal with only one optical axis. These crystals typically belong to the hexagonal or tetragonal crystal systems.
Unit Cell
The smallest three-dimensional volume element from which the crystal can be constructed.
Unit-cell Parameters
The parameters (a, b, c, ?, ?, ?) that define the crystallographic unit cell.
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Van’t Hoff Plot
A plot of the log of solubility values versus the reciprocal of the temperature. The plot for several forms of a substance reveals transition temperatures for the forms.
Void Space
The space within a desolvated crystal that is not occupied by atoms.
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Wallach’s Rule
A rule stating that enantiomeric crystals tend to be more soluble (lower melting) than the corresponding racemic crystals.
Weissenberg Camera
A camera consisting of a cylinder of film that, while a crystal is rotated 180°, is moved past a slit in a screen in one direction along the axis of rotation, then back again through another 180°. The result gives a pattern of intensities that is used to determine the space group and unit-cell dimensions of the crystal.
Wet Etched
A technique for studying surface properties of crystals by eroding their surface with exposure to solvent.
Wg
The weight of a monolayer of water on a solid.
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Xcelodose™
This is a precision powder micro-dosing system which allows pharmaceutical companies to fill capsules with drug substances, providing a shorter drug development process.
X-Ray Diffraction Pattern (X-Ray powder pattern) (XRPD)
The diffraction pattern produced by the lattice spacings in an ordered solid through exposure to X-rays. This technique can be used to identify a substance, ascertain the polymorph(s) present, and determine the crystallinity of a solid.
X-rays
Electromagnetic radiation with a wavelength approximating that of interatomic distances, thus allowing the measurement of these distances.
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Zero-order Kinetics
A rate equation independent of concentration.
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