absorptive dissolution testing
A dissolution test coupled to a membrane that removes dissolved drug into a receiver, as absorption would, so that release, phase behaviour and mass transfer are measured together.
Full page in Mesoporous silica →322 terms with the first sentence of their definition, 89 abbreviations and 101 formulas. The search box also looks through the headlines of all 405 findings.
A dissolution test coupled to a membrane that removes dissolved drug into a receiver, as absorption would, so that release, phase behaviour and mass transfer are measured together.
Full page in Mesoporous silica →A membrane compartment that removes dissolved drug from the dissolution medium while dissolution and phase change go on, as the intestinal wall does in vivo; the test that couples a dissolving donor to such a compartment is called absorptive dissolution testing.
Full page in Bioperformance →Storage at raised humidity and/or temperature to provoke and rank physical instability in less time than at the intended storage condition.
Full page in Physical stability →The transfer of a proton, or the formation of an ion pair, between an acidic and a basic group of drug and polymer, instead of a neutral hydrogen bond.
Full page in Miscibility and drug-polymer interactions →The ratio of the ideal solubility to the real solubility of a drug in a solvent, \gamma_d; a value below 1 means that the drug dissolves better than ideal, far above 1 that it mixes much worse.
Full page in PEG dispersions →A classification of drug/additive pairs by where the additive acts on the amorphous solubility S_a (Ueda 2024, review, pp. 28–40).
Full page in C. Amorphous solubility and LLPS →The shape taken by a polymer chain once it sits on the drug crystal, as trains (segments lying on the surface), loops and tails; more trains mean more surface contact.
Full page in D. Crystallization from solution →The amount of solute held per gram of adsorbent, Q_a (mg/g), against the solute concentration left in solution at equilibrium, C_e, at constant temperature.
Full page in Mesoporous silica →The separation of an amorphous drug–polymer mixture into two amorphous phases of different composition, a drug-rich and a polymer-rich one, shown by two glass transitions or by imaging.
Full page in Miscibility and drug-polymer interactions →The Gibbs free energy of converting the crystal to the amorphous drug (supercooled liquid or glass) at the test temperature; it fixes the factor e^{\Delta G/RT} of the amorphous solubility.
Full page in C. Amorphous solubility and LLPS →The amorphous form of a drug salt; salt formation adds an ionic interaction between the protonated base and the counterion, taken to dominate over hydrogen bonding in setting Tg.
Full page in Crystallization tendency →A drug dispersed in a polymer in the amorphous state to raise dissolution rate and supersaturation.
Full page in C. Amorphous solubility and LLPS →The factor by which the amorphous drug is more soluble than the crystal, e^{\Delta G/RT} from the crystal–amorphous free-energy difference, reduced by the activity of the water-saturated amorphous drug.
Full page in C. Amorphous solubility and LLPS →The concentration of dissolved drug at which a supersaturated aqueous solution is in apparent, metastable equilibrium with the amorphous drug, more rigorously with the water-saturated supercooled liquid or glass; it is not a true thermodynamic solubility, which is why the authors keep it in quotation marks.
Full page in C. Amorphous solubility and LLPS →The presence of both hydrophobic and hydrophilic parts in one molecule.
Full page in D. Crystallization from solution →The rise of the Tg of a drug on mixing in a polymer of higher Tg, and with it a lower mobility, proposed as a reason for the stabilization of amorphous dispersions.
Full page in Miscibility and drug-polymer interactions →Phase separation in which the insoluble phase is enriched in both drug and polymer, a complex coacervate, against segregative separation in which the polymer stays in the aqueous phase.
Full page in A. Release mechanism and LoC →Deposition of a thin metal-oxide film on the surface of powder particles by repeated, self-limiting vapour-phase reactions in a rotating reactor.
Full page in ASD process →A DSC method from inorganic glass science to estimate the critical cooling rate: the natural logarithm of the cooling rate is regressed on 1/\Delta T^2, where ΔT is the undercooling at the crystallization peak, and Rcrit is taken as \exp(A), the extrapolated rate at which no crystallization would be seen.
Full page in Crystallization tendency →Dark bands in a TEM image where a thin, bent crystal meets the diffraction condition; they mark curvature, here read as strain at the crystal–matrix interface.
Full page in ASD process →A multilayer adsorption isotherm in which the first layer is held most strongly and further layers more weakly, with no lateral interactions and a homogeneous surface.
Full page in Mesoporous silica →The Bravais–Friedel–Donnay–Harker prediction of crystal shape from the crystal structure alone (lattice and symmetry, without growth conditions or additives).
Full page in D. Crystallization from solution →The number and position of hydroxyl groups on the steroid of a bile salt, which with the glycine or taurine conjugate defines the bile salt: cholates (STC, SGC) carry three hydroxyl groups, deoxycholates (STDC, SGDC) and chenodeoxycholates (STCDC, SGCDC) two, at different positions.
Full page in D. Crystallization from solution →Aggregates of bile salt above its critical micelle concentration; in the telaprevir studies 1.86 mM is nominally the monomer and 12 mM the micellar level, with micelles of the dihydroxy salts STDC, SGDC and STCDC opposing the monomer effect on nucleation and those of STCDC and SGCDC on growth.
Full page in D. Crystallization from solution →The equilibrium constant of the association of a drug molecule with a polymer group, here the indomethacin–PVP carbonyl species.
Full page in Miscibility and drug-polymer interactions →The coexistence curve of the water-rich and the drug-rich liquid phases: beyond it two liquid phases can coexist, and at a fixed temperature its concentration is the LLPS (coexistence) concentration CL-L; the spinodal lies inside it.
Full page in C. Amorphous solubility and LLPS →Dissolution media that simulate gastrointestinal fluids (FaSSIF, FeSSIF, Ensure Plus for the fed stomach).
Full page in Bioperformance →The ability of a medium to take up acid or base with little change of pH, given in mM per pH unit (mM/ΔpH).
Full page in A. Release mechanism and LoC →Thermodynamic rules for polymorph pairs; the heat-of-fusion rule used in the library says that if the higher-melting form also has the larger heat of fusion, the pair is monotropic.
Full page in Crystallization tendency →The partial molar free energy of the drug in a phase.
Full page in C. Amorphous solubility and LLPS →The handedness of a drug molecule, and with it the difference between a single enantiomer and the racemate as a solid form and as a solute.
Full page in B. Supersaturation from ASD dissolution →The theory that writes the nucleation rate as a pre-exponential factor times \exp\left, with a thermodynamic barrier W^* = \frac{16\pi\sigma^3}{3\,\Delta G_v^2} for a spherical nucleus and an activation energy for viscous flow.
Full page in Crystallization tendency →How completely and evenly an atomic layer coating covers the surface of a particle, without gaps, thin spots or uncoated regions.
Full page in ASD process →The number and size of pinholes, cracks and voids in an atomic layer coating through which water and medium reach the particle.
Full page in ASD process →Crystallization on heating a glass into its supercooled liquid (devitrification), as opposed to melt crystallization on cooling.
Full page in Crystallization tendency →The entropy part of the Flory–Huggins activity coefficient and free energy, set by molecular size alone.
Full page in Miscibility and drug-polymer interactions →Two additives competing for the same adsorption sites on a crystal, so that the pair does no better than the stronger one, or a surfactant displacing a polymer so that the polymer's inhibition is lost.
Full page in D. Crystallization from solution →The ability of a molecule to take different shapes by rotation about single bonds, counted in the library as the number of rotatable bonds.
Full page in Crystallization tendency →Drug and polymer leave a dispersion at the same normalised rate, so release is governed by the polymer; typical of low drug loading, and the condition for fast, complete release of a copovidone dispersion.
Full page in ASD process →The change of a solute's solubility in a mixture of two solvents with their ratio; in this chapter water is an anti-solvent for hydrophobic drugs, and polymer plus sorbed water is treated as the drug's co-solvent inside a humid dispersion.
Full page in Physical stability →An ideal-mixing prediction of the Tg of a miscible blend in which the constant is the ratio of the heat-capacity steps of the components at their Tg; a measured Tg below the line is read as non-ideal mixing.
Full page in Physical stability →Rcrit (Rcrit,cool) is the slowest cooling of a melt that avoids detectable crystallization; the rate that avoids any nucleation, RNcrit, is faster still, and cooling between the two leaves nuclei in the glass.
Full page in Crystallization tendency →The molecular weight above which chains of a polymer entangle.
Full page in A. Release mechanism and LoC →Rcrit,heat, the slowest reheating of a glass through the undercooled melt that avoids crystallization.
Full page in Crystallization tendency →The minimum fraction of the acid groups of an enteric polymer that must be ionized before its chains dissolve; below it the polymer does not dissolve, or dissolves slowly, whatever the bulk pH. In the Miscibility chapter it was written with the Willson model, dissolution rate ∝/, and used to explain why CAP and HPMCP dispersions with a basic drug that ties up some acid groups release poorly or slowly.
Full page in A. Release mechanism and LoC →The surfactant concentration above which micelles form; Tween 80 was used above its CMC of 23.6 µg/mL (0.018 mM).
Full page in C. Amorphous solubility and LLPS →The smallest cluster that grows instead of dissolving; the induction time is defined as the time to form a critical nucleus plus the time for it to grow to a detectable size.
Full page in D. Crystallization from solution →The point on the binodal of a ternary diagram at which the two coexisting phases have the same composition; the 2023 dissolution papers call it the plait point.
Full page in A. Release mechanism and LoC →The radius \rho_c below which a two-dimensional island on a crystal face cannot grow; it falls as the supersaturation rises, \rho_c = \gamma a/(kT \ln S) (Gibbs–Thomson), and it decides whether adsorbed impurities pin a step: growth is arrested when the spacing of adsorbed molecules equals 2\rho_c.
Full page in D. Crystallization from solution →Imperfections in a crystal (vacancies, impurities, dislocations, grain boundaries, growth irregularities) that are higher-energy, more mobile sites, may start phase transformations, have been linked to faster dissolution and impose local stress.
Full page in ASD process →The process by which drug crystals suspended in a softened polymer dissolve into it, below the drug's melting point and above the polymer Tg, forming the homogeneous melt that becomes an ASD on cooling.
Full page in ASD process →Reduction of the crystal growth rate by an additive, here dissolved PVPVA or HPMCAS, expressed as the effectiveness ratio E_G=R_{G,np}/R_{G,p}, the growth rate without polymer over the rate with it.
Full page in ASD process →The power law R_G = k_G S^g (with an area factor in one paper, R_G = A k_G S^g), the growth rate rising with the supersaturation ratio through a coefficient and an empirical order g between 1 and 2.
Full page in D. Crystallization from solution →The speed at which a crystal front advances into the surrounding supercooled liquid or glass, taken as the slope of crystal size (length, radius or diameter) against time.
Full page in Crystallization tendency →The second step of crystallization: existing nuclei or seeds grow by molecules crossing the crystal–liquid interface and attaching to growth sites.
Full page in Crystallization tendency →The outer shape of a crystal, here described by length, width and aspect ratio (mean length over mean width) of 50 crystals per sample; additives that adsorb on and slow the fastest-growing faces change it.
Full page in D. Crystallization from solution →The free energy per area of the interface between a crystal (or nucleus) and its own supercooled melt or glass; in classical nucleation theory it sets the surface penalty of a nucleus, and in the two-dimensional nucleation model of growth it sets the barrier for a new layer.
Full page in Physical stability →Crystals already present in a dispersion or added to the medium act as templates for growth and consume supersaturation; the relevant property is the growth area and interface structure of the seeds, not their mass.
Full page in ASD process →The equilibrium solubility of the stable crystalline form of the free drug in a given medium, the reference against which supersaturation and the amorphous advantage are defined; Eq. 1 multiplies it by the free-energy and water terms to obtain the amorphous solubility.
Full page in C. Amorphous solubility and LLPS →Crystallization of an amorphous drug while it dissolves, either on the dissolving solid or from the supersaturated solution it creates, so that the solution never reaches the calculated amorphous solubility.
Full page in D. Crystallization from solution →Crystallization of a drug melt as it is cooled below Tm, or while it is held below Tm; it is the route probed by the DSC classification and the one relevant to melt extrusion and melt quenching.
Full page in Crystallization tendency →The delay or slowing of crystallization of an amorphous drug by a polymer mixed with it.
Full page in Miscibility and drug-polymer interactions →A sorting of neat drugs by when, if ever, they crystallize under a fixed protocol.
Full page in Crystallization tendency →The propensity of an amorphous or supercooled drug to crystallize, expressed as a class from the melt or after solvent evaporation, as a growth rate, or as a time to crystallize in storage or solution.
Full page in Crystallization tendency →In this chapter, the formation of crystals from a supersaturated solution or from a drug-rich phase; it depletes the supersaturation, unlike a drug-rich phase, which keeps it.
Full page in Solution methods →The combined effect of time and temperature on degradation, which "must be considered when developing HME formulations and manufacturing processes".
Full page in ASD process →The temperature at which a thermogravimetric ramp is said to show the start of degradation (T_onset, T_deg), read either as the tangent intersection of the baseline and the mass-loss curve or as the temperature of 0.1, 0.5 or 1.0% mass loss.
Full page in ASD process →The share of a sample that is crystalline.
Full page in Solid-state methods →The average number of the three hydroxyl groups of an anhydroglucose unit of cellulose that carry a given substituent (maximum 3); DS (CO2H) counts the substituents that end in a free carboxyl (adipate, suberate, sebacate).
Full page in D. Crystallization from solution →\Delta T = T_m - T, how far below its melting point a liquid is held or crystallizes; "undercooling" and "supercooling" are used as synonyms.
Full page in Crystallization tendency →The fall of the dissolved concentration after supersaturation was reached, because crystals nucleate or seeds grow; in an ASD it "corresponds to the crystal growth rate exceeding the dissolution rate".
Full page in ASD process →The smallest feature that a light microscope or optical spectroscopy can resolve, set by the wavelength and the numerical aperture.
Full page in Solid-state methods →The thin region at a dissolving surface across which drug moves by diffusion.
Full page in ASD process →Crystal growth whose rate is limited by transport of molecules to the crystal surface rather than by their incorporation into the lattice.
Full page in Physical stability →Slowing of crystallization simply because the polymer dilutes the drug, which would scale directly with the polymer volume fraction.
Full page in Physical stability →Electrostatic interaction between permanent dipoles, proposed in this chapter as the contact of ketoconazole with PVP, since ketoconazole has no hydrogen-bond donor and its PVP carbonyl does not shift: "it seems reasonable to speculate" that the two interact through dipole–dipole forces, helped by the large size of ketoconazole and its van der Waals contacts.
Full page in Miscibility and drug-polymer interactions →Absorption limited by slow dissolution of the dose.
Full page in Bioperformance →The merging of drug-rich droplets into larger ones; the growth of the ritonavir droplets from about 345 to about 842 nm in 64 min is "consistent with coalescence of the droplets, commonly observed in LLPS".
Full page in C. Amorphous solubility and LLPS →Uptake of dissolved drug onto a silica surface.
Full page in Mesoporous silica →Dissolution paced by the drug itself, slow and typical of high drug loading, in which the driving force vanishes once the amorphous solubility is reached and no droplets form.
Full page in ASD process →Mixing of two drugs in one amorphous phase; it makes a mixed drug-rich phase when both dissolve.
Full page in Bioperformance →Passage of drug, and of polymer, out of suspended ASD particles into the surrounding liquid while the particles stay largely undissolved, as in acid for dispersions of enteric polymers.
Full page in B. Supersaturation from ASD dissolution →The weight fraction of drug in an ASD (10, 30, 50% in the earlier papers).
Full page in Bioperformance →Association of drug and polymer in aqueous solution into a complex, which can raise the apparent solubility of the drug or, if the complex is insoluble, take drug and polymer out of solution.
Full page in B. Supersaturation from ASD dissolution →A hydrogen bond between a donor group of the drug (NH, OH or COOH) and an acceptor of the polymer, in PVP and PVPVA the carbonyl of the vinylpyrrolidone unit, read from a shift of the polymer carbonyl band to lower wavenumber.
Full page in A. Release mechanism and LoC →The contacts between drug and polymer in an amorphous dispersion, relative to the contacts in the pure components: strong adhesive (drug–polymer) interactions formed at the expense of weak cohesive (self) interactions make mixing exothermic, adhesive interactions that require breaking strong cohesive ones do not.
Full page in Miscibility and drug-polymer interactions →Electrostatic attraction between an ionized drug and oppositely charged groups of the dispersion polymer, here a weakly basic drug cation and the carboxylate of an enteric polymer.
Full page in A. Release mechanism and LoC →A single amorphous phase formed by liquid–liquid mixing of amorphous drug and amorphous polymer, a description the authors themselves call "clearly" an oversimplification below Tg, where the system is not at equilibrium.
Full page in Miscibility and drug-polymer interactions →Whether drug and polymer stay mixed once water enters the dispersion.
Full page in A. Release mechanism and LoC →A drug-rich layer at the dissolution front that blocks release of the drug and of the polymer beneath it.
Full page in A. Release mechanism and LoC →The dispersed drug-rich phase formed by LLPS, usually of 100–300 nm, which dissolves fast and is expected to replenish absorbed drug.
Full page in Bioperformance →The growth of a separated drug-rich phase into fewer, larger domains or droplets after it has formed, in the hydrated dispersion or in the medium.
Full page in A. Release mechanism and LoC →The dispersed, non-crystalline phase that forms when a supersaturated drug solution phase-separates above the amorphous solubility: a water-saturated supercooled liquid or, for high-Tg drugs, a glass, that can later crystallize; "drug-rich phase" is judged a more appropriate term than "precipitate".
Full page in Solution methods →A polymer-depleted, drug-enriched layer at the surface of a dissolving ASD, left when the polymer dissolves ahead of the drug above the limit of congruency.
Full page in ASD process →A hydrogen bond between a surface silanol (Si–OH) as donor and an acceptor group of the drug, a carbonyl or a ring nitrogen.
Full page in Mesoporous silica →The amount of crystalline drug that a polymer can hold in solution at a given temperature.
Full page in ASD process →A reversible exchange between drug adsorbed on silica and drug in solution, written as adsorbed drug + solvent in solution ⇌ adsorbed solvent + drug in solution: water displaces drug from the surface, and more drug in solution shifts the balance toward the adsorbed side.
Full page in Mesoporous silica →A polymer with acidic groups, such as the succinoyl groups of HPMCAS, the phthalyl groups of HPMCP or the methacrylic acid of the Eudragit L grades, that stays largely undissolved at gastric pH and dissolves above a threshold pH set by its substitution.
Full page in B. Supersaturation from ASD dissolution →The heat absorbed when a crystal melts (ΔHfus, heat of fusion), measured by DSC; with Tm it gives the entropy of fusion and the Hoffman estimate of the crystallization driving force, and with the melting points of two polymorphs it decides monotropy by the heat-of-fusion rule.
Full page in Crystallization tendency →The heat effect of mixing drug and solvent or polymer, set by the strength of the cross (adhesive) interactions relative to the interactions in the pure components.
Full page in PEG dispersions →The slow loss of excess enthalpy of a glass during ageing below Tg, recovered as an endotherm on reheating; fitted with a stretched exponential, it gives a mean relaxation time τ (longer means less mobile) and a width parameter β.
Full page in Physical stability →The entropy gained on melting, \Delta S_{fus} = \frac{\Delta H_{fus}}{T_m} with Tm in kelvin.
Full page in Crystallization tendency →The entropy gained when drug and polymer mix.
Full page in Miscibility and drug-polymer interactions →Empirical rules from crystal engineering on which donors and acceptors pair in a crystal: all good proton donors and acceptors are used in hydrogen bonding; intramolecular hydrogen bonds that close a six-membered ring form in preference to intermolecular ones; and the best donors and acceptors left after intramolecular bonding pair with one another.
Full page in Miscibility and drug-polymer interactions →The composition (the eutectic composition) and temperature at which a mixture of two components that mix fully as liquids and not as solids melts at its lowest temperature.
Full page in PEG dispersions →A risk classification that combines the DSC nucleation behaviour with the crystal growth rate: class IA (high nucleation and growth, overlapping zones, crystallizes on cooling), IB (high nucleation and growth, little overlap; good glass-forming ability, poor glass stability), II (rapid growth, low nucleation), III (ready nucleation, slow growth) and IV (slow nucleation and growth).
Full page in Crystallization tendency →The steep fall of drug release over a small increase of drug loading just above the limit of congruency, named "falling off a cliff" for ritonavir–PVPVA, whose drug release at 60 min fell from ≈97% at 25% loading to ≈29% at 30% and below ≈2% at 35–50%.
Full page in A. Release mechanism and LoC →Steady-state diffusive flux through a membrane written in activity form, J = D S a/(h \gamma_m); the concentration form is J = (D_{eff}/l)(C_d - C_r).
Full page in Bioperformance →The parameter \chi of Flory–Huggins lattice theory that expresses the energy of drug–polymer contacts relative to the contacts in the pure components.
Full page in PEG dispersions →Lattice solution theory for a small molecule and a polymer, used here with the amorphous drug treated as the solvent and one lattice site set equal to the molecular volume of the drug (or, in the 2009 paper, of a liquid analogue of PVP).
Full page in Miscibility and drug-polymer interactions →The change of release or exposure when a dose is taken with food rather than fasting.
Full page in B. Supersaturation from ASD dissolution →The formulation critical temperature (Tc, also called the solubility temperature) is the lowest temperature at which a homogeneous molecular dispersion of a given drug–polymer composition can in theory form, because all drug crystals can dissolve; for 1:1 IDM–PVPVA it is 131 °C by the Flory–Huggins prediction and 132.3 ± 0.8 °C measured.
Full page in ASD process →1/T_g = w_1/T_{g,1} + w_2/T_{g,2} for the glass transition of a miscible blend.
Full page in Bioperformance →How steeply molecular mobility or viscosity changes as a liquid approaches Tg: strong liquids follow Arrhenius behaviour, fragile ones depart from it.
Full page in Crystallization tendency →The concentration of molecularly dissolved drug that can cross a membrane, as against drug in micelles, complexes, droplets or aggregates.
Full page in Bioperformance →The free energy change on mixing drug and polymer, ΔGmix = ΔHmix − TΔSmix: a negative ΔGmix with one minimum versus composition means complete miscibility, a positive ΔGmix complete immiscibility, and two minima (the binodal points) with a metastable region between them and an unstable region bounded by the spinodal points partial miscibility; this liquid-mixture theory is extended by the authors to amorphous solids.
Full page in Miscibility and drug-polymer interactions →An empirical power-law isotherm, Q_a = K_F C_e^{1/n}, used for heterogeneous surfaces and multilayer adsorption; the papers fit its linear logarithmic form.
Full page in Mesoporous silica →The spread of stomach pH between and within patients, from about 1.6 fasted to 5 or above after a meal, and with age or acid-reducing drugs, which changes how much drug and polymer dissolve during the gastric stage of a dispersion and how long the dispersion sits wetted before the pH rises.
Full page in B. Supersaturation from ASD dissolution →The swollen, porous, polymer- and water-rich layer that forms at a hydrating ASD surface, below any drug-enriched outer layer, and from which the polymer disentangles into the medium.
Full page in ASD process →The relation between the changes of chemical potential of the components of a mixture; integrated with the measured water activity against composition from a sorption isotherm, it gives the activity of the drug in the water-saturated amorphous phase, the term e^{-I(a_2)} of the amorphous solubility estimate (the Murdande method).
Full page in C. Amorphous solubility and LLPS →In the library, glass-forming ability (GFA) is the ease with which a melt vitrifies on cooling instead of crystallizing; a compound that crystallizes during a controlled DSC cooling (class I) has a low GFA. It is kept apart from glass stability, the resistance of the glass to crystallization on reheating or storage.
Full page in Crystallization tendency →The boundary between the dry glassy core of a dissolving compact and the swollen, rubbery gel layer.
Full page in A. Release mechanism and LoC →Phase separation of a supersaturated solution into a water-rich phase and a drug-rich phase that is a glass at the test temperature, because its water-plasticized Tg lies above that temperature; the term was judged "more appropriate" than LLPS for atazanavir (Tg of the precipitate about 51 °C at 37 °C).
Full page in C. Amorphous solubility and LLPS →Combinations of Tg, the onset and peak of crystallization on reheating and Tm (KLL, KH, KW, KSP, K1, K2 and the reduced temperature Tred), taken from inorganic glass science; a larger gap between Tg and crystallization onset "generally" means a better glass former.
Full page in Crystallization tendency →The resistance of a glass, or of the liquid formed when it is reheated above Tg, to crystallization; the authors of the 2010 classification call the term "somewhat of a misnomer" because it is usually judged by reheating rather than by the glass itself.
Full page in Crystallization tendency →The temperature that separates the glass from the supercooled liquid; it is a kinetic transition where the system falls out of equilibrium.
Full page in Crystallization tendency →The relation T_g=(w_1T_{g1}+Kw_2T_{g2})/(w_1+Kw_2) for the Tg of a miscible binary blend from the weight fractions and Tgs of its components, with K either from true densities and Tgs (Simha–Boyer form, K=\rho_1T_{g1}/\rho_2T_{g2}) or fitted.
Full page in ASD process →The interface between regions of a crystal of different orientation; in IDM crystals unheated in copovidone, grain boundaries divided a flat crystal into three regions whose diffraction contrast moved independently on refocusing, taken as proof of three orientations.
Full page in ASD process →An adsorbed additive covering the sites where growth units attach (kinks on step edges), so that less of the surface is open to growth; HPMCAS globules at pH 3 leave many sites open, a flat chain at pH 6.8 is said to block more than one, and monomeric STCDC is said to block telaprevir growth.
Full page in D. Crystallization from solution →A non-covalent interaction between a halogen atom (Cl, Br, I) of a drug and an electron donor, in PVP and PVPVA the amide carbonyl oxygen of the vinylpyrrolidone unit (I···O=C).
Full page in A. Release mechanism and LoC →The relation between pH, pKa and the ratio of un-ionized to ionized drug, \mathrm{pH} = \mathrm{p}K_a + \log_{10}(/) for a weak base.
Full page in C. Amorphous solubility and LLPS →Nucleation at an interface (a foreign particle, a container wall, a second phase), which lowers the nucleation barrier, so nucleation there proceeds more readily.
Full page in Crystallization tendency →A core amorphous dispersion particle with an additional water-soluble component coating its surface.
Full page in A. Release mechanism and LoC →The diffusion-controlled model of Higuchi and co-workers (cited) for a non-interacting, non-disintegrating mixture of two components: the composition of the dissolving interface stays constant only at one critical mixture ratio; at any other ratio the surface enriches in one component, which then controls dissolution, and for components of very different solubility the drug fraction that gives polymer control is very low.
Full page in A. Release mechanism and LoC →A map of product melt temperature against residence time for hot melt extrusion with regimes: thermal degradation at the top, melting above the drug's melting point, dissolution between Tc and Tm (the drug dissolves into the softened polymer, not melts) and suspension below Tc, plus an inaccessible zone below the polymer's minimum processing temperature.
Full page in ASD process →An approximation for the free-energy difference between the supercooled liquid and the crystal at a temperature T below Tm, needing only Tm and the heat of fusion.
Full page in Crystallization tendency →The strength of a group as a hydrogen-bond acceptor.
Full page in Miscibility and drug-polymer interactions →The groups of a drug or polymer that can give a hydrogen bond (NH, OH, COOH) or take one (carbonyl, ether or hydroxyl oxygen, amine nitrogen), and their relative strengths; used to choose a polymer whose strongest group complements a free group of the drug.
Full page in Physical stability →In the papers of this chapter, a bond between a donor group of the drug (the carboxylic acid OH of indomethacin, the NH of felodipine and nimesulide, hydroxyl groups of sucrose) and an acceptor group of the polymer (the lactam carbonyl of PVP, the acetate groups of PVAc and PVP/VA, the carboxyl of PAA, the groups of HPMCAS), or between molecules of the same kind (acid dimers of the drug, self-association of PAA).
Full page in Miscibility and drug-polymer interactions →The balance of hydrophilic and lipophilic parts of a surfactant, used in the library to rank surfactants from hydrophobic (Span 85) to hydrophilic (SDS).
Full page in A. Release mechanism and LoC →The release of the ordered, "iceberg-like" water around apolar groups when a solute leaves the water, which costs enthalpy and gains entropy.
Full page in C. Amorphous solubility and LLPS →The association of non-polar drug molecules to minimize contact with water; Ilevbare and Taylor call it "intuitive" that LLPS of drugs with Log P 2.24–5.98 is driven by hydrophobic interactions and attribute the lower LLPS concentration at higher ionic strength to salting-out, which strengthens them ("may be attributed").
Full page in C. Amorphous solubility and LLPS →The pairing of an ion with an oppositely charged amphiphile into a poorly soluble complex, driven by electrostatic attraction and hydrophobic interaction; ionic polymers form such insoluble complexes with oppositely charged amphiphiles.
Full page in A. Release mechanism and LoC →The tendency of a drug to avoid water, read in the library from its calculated log P; for the moisture-separation papers a hydrophobic drug is expected to have a positive water–drug interaction parameter, so that sorbed water makes the dispersion less favourable for it.
Full page in Physical stability →How much water a material takes up at a given humidity.
Full page in ASD process →Entropy-driven mixing of two amorphous components in the drug-rich phase with no heat of mixing, so that the chemical potential of each falls by RT\ln x and its amorphous solubility becomes the pure-drug value times its mole fraction in that phase.
Full page in C. Amorphous solubility and LLPS →The solubility a crystalline drug would have if it mixed ideally with the solvent; it is set by the melting temperature and the enthalpy of fusion alone.
Full page in PEG dispersions →The factor α of the Kubota–Mullin model that says how strongly a given surface coverage by an adsorbed impurity slows crystal growth; α = 1 means growth stops at full coverage, α above 1 means growth stops before the surface is covered, and α near 0 means no reduction at any concentration.
Full page in D. Crystallization from solution →Forming the drug salt in the same solution and evaporation or drying step that forms the dispersion, so that drug, counterion and polymer are processed together and the dispersion contains the protonated drug.
Full page in B. Supersaturation from ASD dissolution →The relation between an in vitro test and in vivo performance.
Full page in Bioperformance →Release that stops below the dose although the drug has not crystallized; in the library it is the defining problem of drug-loaded mesoporous silica under supersaturating conditions.
Full page in Mesoporous silica →Polymer and drug leave the dispersion at different rates; above the limit of congruency the polymer leaves first, the undissolved solid becomes drug-rich and release slows.
Full page in ASD process →A precipitate of drug and dissolved polymer that forms when both meet in buffer at a pH where the polymer alone stays dissolved, so that polymer in the pellet marks a complex.
Full page in A. Release mechanism and LoC →Crystal growth limited by the incorporation of molecules into the lattice at the surface, not by their transport to it; in the empirical law R_G = k_G S^{g} an overall order g of 1 means diffusion control and 2 integration control, with measured orders usually between 1 and 2.
Full page in D. Crystallization from solution →The free energy per unit area (or length of a step edge) of the interface between a crystal or nucleus and the solution; a lower value gives a smaller critical nucleus and faster nucleation or growth, and the authors use it to explain why SDS speeds felodipine growth.
Full page in D. Crystallization from solution →A hydrogen bond between two groups of the same molecule.
Full page in Miscibility and drug-polymer interactions →The dissolution rate per unit area of a compact of one pure material, with one face of fixed area exposed; for a dispersion each component's rate divided by its weight fraction gives the rate per area "as if it were the pure material".
Full page in A. Release mechanism and LoC →The solubility of the neutral (un-ionized) form of an ionizable drug in equilibrium with its stable crystal; in the pH-titration work it is the neutral-species concentration at the point where the pH gradient crosses zero, so that there is no net dissolution or precipitation.
Full page in D. Crystallization from solution →Attraction or repulsion between charged species.
Full page in Mesoporous silica →The fraction of a drug that carries a charge at the pH of the medium, set by the pKa through the Henderson–Hasselbalch equation.
Full page in C. Amorphous solubility and LLPS →The activation energy for moving molecules across the nucleus–matrix interface, \Delta G_a in classical nucleation theory, related to diffusivity or reciprocal viscosity; distinct from the thermodynamic barrier set by interfacial energy and driving force.
Full page in Physical stability →Stabilization of an amorphous drug against crystallization by slowing the process (molecular mobility, nucleation, interfacial factors) while the thermodynamic driving force stays large.
Full page in Miscibility and drug-polymer interactions →A state that persists because molecular mobility is too low for the system to reach its equilibrium state; here, a glassy dispersion whose phase state, mixed or separated, was fixed by how it was made.
Full page in Miscibility and drug-polymer interactions →Growth of a crystal from a supercooled liquid needs both mobility and a driving force: near Tm mobility is high and the driving force low (thermodynamic control), and on cooling the driving force rises while mobility falls (kinetic control).
Full page in Physical stability →The stretched-exponential description of relaxation, 1 - \phi(t) = \exp\left(-(t/\tau)^{\beta}\right), used in the library to fit the enthalpy recovered by aged glasses and dispersions; τ is a mean relaxation time and β a width parameter between 0 and 1.
Full page in Physical stability →Adsorption into a single layer on identical, independent sites, rising to a saturation capacity Q_m.
Full page in Mesoporous silica →The rule that gives the relative amounts of two coexisting phases from the position of the overall composition on the tie line joining them: the ratio of the amount of phase A to phase B equals the ratio of the lengths BX to AX. In the Physical stability chapter it was used on a schematic ritonavir–PVPVA–water diagram to argue that relative phase amounts set bicontinuous or discrete morphology along different hydration paths.
Full page in A. Release mechanism and LoC →Particles suspended in a solution remove light from a beam by scattering and, if they absorb, by absorption; the sum is the extinction.
Full page in Solution methods →The highest drug loading at which a dispersion still releases drug and polymer congruently; for ritonavir–PVPVA it is 25% DL. The ritonavir spray-drying paper uses it as the reference point: phase separation has its largest effect on release at or below the limit, and above it release is already as slow as the neat amorphous drug.
Full page in ASD process →The smallest crystalline (or amorphous) content that can be told from zero by a method.
Full page in Solid-state methods →The smallest content that can be measured with acceptable precision, taken as ten standard deviations of a pure-form reading, from the residual standard deviation of a regression or at a signal-to-noise ratio of 10:1.
Full page in Solid-state methods →The affinity of a drug for lipid over water, written as log P of the neutral species.
Full page in Bioperformance →The splitting of a highly supersaturated aqueous drug solution into a water-rich continuous phase and a dispersed, non-crystalline drug-rich phase, before crystals form; the authors call it glass–liquid phase separation when the drug-rich phase is a glass.
Full page in C. Amorphous solubility and LLPS →The assumption that phase separation in a hydrating dispersion is at least as fast as water penetration, so that the phases at each depth of the gel layer are in pseudo-equilibrium with the local water content and their compositions can be read from the equilibrium ternary diagram.
Full page in A. Release mechanism and LoC →Crystallisation of the amorphous solid itself while it is in contact with the medium, before the drug has dissolved (also called solid-mediated crystallisation), in competition with dissolution and with crystallisation from solution.
Full page in ASD process →The highest crystal growth rate of a compound over temperature (MCV), reached at Tcryst,max between Tg and Tm; below Tcryst,max growth is limited by mobility, above it by the shrinking driving force.
Full page in Crystallization tendency →The steady-shear viscosity of a drug melt at Tm (ηmelt) and below it in the undercooled range; its rise on cooling is expressed as the ratio \eta/\eta_{melt}.
Full page in Crystallization tendency →The lowering of the melting temperature of a crystalline component by the second component of a miscible mixture.
Full page in PEG dispersions →The rate at which drug crosses a membrane in a side-by-side diffusion cell, taken as the slope of the receiver concentration against time; with diffusion coefficient, area, thickness and membrane activity coefficient constant, it is proportional to the donor activity.
Full page in C. Amorphous solubility and LLPS →The overall coefficient K_in (cm/s) of a hollow-fibre module, the sum of three resistances in series; independent of the donor concentration in theory.
Full page in Bioperformance →Passive transfer of dissolved drug across a membrane; in these papers a measure of free drug or activity.
Full page in Bioperformance →The state in which the drug-rich and the drug-lean phases coexist with equal activity while both remain supersaturated with respect to the crystal.
Full page in Bioperformance →The range of supersaturation in which a solution is supersaturated with respect to the crystal but does not nucleate spontaneously, so that existing crystals can grow while new ones hardly form; above it lies the labile zone of spontaneous nucleation.
Full page in B. Supersaturation from ASD dissolution →Increase of the apparent solubility of a drug by incorporation into surfactant micelles; with Tween 80 above its CMC, ritonavir's crystalline solubility rose 2.7-fold and its LLPS concentration about 2.5-fold (synthesis: 46.1 ÷ 18.8 = 2.45), leaving their ratio about unchanged.
Full page in C. Amorphous solubility and LLPS →The pH at a dissolving surface, in its gel layer or in the adjacent boundary layer, which can differ from the bulk pH. When an acidic polymer dissolves above its pKa, ionization releases protons and lowers the interfacial pH, which can lower solubility and dissolution; the protons leave by diffusion, by neutralization with hydroxyl ions from the bulk or through proton carriers (buffer species), and finite diffusion times give a surface-to-bulk gradient set by hydrodynamics, the pKa and solubility of the solute and the pKa and concentration of the buffer (cited).
Full page in A. Release mechanism and LoC →Aggregates of bile salts with phospholipids and their hydrolysis products, the good drug solubilizers of intestinal fluid; the bile-salt papers worked with single bile salts and name mixed micelles with lecithin as the next, more biorelevant step.
Full page in D. Crystallization from solution →Reduction of the uptake of water, or of its rate, by a particle coating.
Full page in ASD process →Crystallization of an amorphous drug, alone or in a dispersion, that sorbed water starts or speeds up.
Full page in Physical stability →Splitting of an initially miscible drug–polymer dispersion into drug-rich and polymer-rich amorphous phases because of water, either taken up during storage or present during preparation.
Full page in ASD process →How fast molecules of an amorphous solid move and rearrange, the kinetic side of crystallization next to the driving force.
Full page in Physical stability →The specific fit between molecules that lets them assemble in a given arrangement; in crystal engineering hydrogen bonding is the most reliable directional interaction for it.
Full page in Physical stability →The amount of adsorbate that covers a surface with one layer.
Full page in Mesoporous silica →A crystalline dispersion in which drug and polymer mix fully as liquids and not as solids, and the drug has minimal solubility in the molten polymer and causes a negligible depression of the polymer melting point; the liquidus of the drug rises steeply from the PEG side.
Full page in PEG dispersions →A polymorph pair in which one form is the more stable at every temperature up to melting, so the other can only convert into it; the free-energy curves would cross only at a virtual transition temperature above both melting points.
Full page in Crystallization tendency →Adsorption beyond one layer of adsorbate on the surface.
Full page in Mesoporous silica →The state of drug held in pores a few nanometres wide, where in the literature view it resists crystallization, especially below the critical nucleus size, has a lower melting temperature and is held by the pore wall.
Full page in Mesoporous silica →The joining of drug-rich droplets into clusters or networks.
Full page in A. Release mechanism and LoC →The proposal that the drug-rich phase replenishes drug absorbed from the water phase, keeping the activity and flux at their maximum for as long as it lasts.
Full page in C. Amorphous solubility and LLPS →The diffusion-layer form of the dissolution rate, dC/dt = (DA/Vh)(C_s - C), with diffusion coefficient D, surface area A, medium volume V, diffusion-layer thickness h and the solubility C_s of the solid form at the dissolving surface.
Full page in A. Release mechanism and LoC →The widening of the NMR peaks of a species that moves between two environments, here ibuprofen exchanging between the aqueous phase and the drug-rich phase.
Full page in C. Amorphous solubility and LLPS →A crystal whose structure has no inversion centre.
Full page in Solid-state methods →Dissolution at a dose that would exceed the crystalline solubility if it all dissolved, so that supersaturation can build up and the competing kinetics of dissolution, nucleation and crystal growth can be seen; non-sink testing is called essential for supersaturating systems and more sensitive to crystals than most solid-state methods.
Full page in ASD process →The dissolution-rate relation dC/dt = (DA/hV)(C_s-C) (diffusion coefficient D, surface area A, boundary-layer thickness h, liquid volume V, solubility C_s): in the ASD process chapter it is applied to crystals dissolving in a polymer melt, where higher temperature and plasticisation by dissolved drug raise D, smaller particles raise A and shear thins h.
Full page in ASD process →The two steps of crystallization, the formation of new crystals and the growth of existing ones; they have different temperature windows and can respond differently to the same additive, and overall crystallization of a powder is nucleation followed by growth.
Full page in Physical stability →The time from creating a supersaturation until crystals are first detected, t_{ind} = t_n + t_g: the time to form stable nuclei plus the time for them to grow to a detectable size; if growth is quick, t_{ind} \propto J^{-1} and a longer time means a slower nucleation rate.
Full page in D. Crystallization from solution →The slowing of crystal nucleation from a supersaturated solution by an additive, measured as a longer nucleation induction time or a lower nucleation rate.
Full page in D. Crystallization from solution →The number of stable crystal nuclei formed per unit volume and time, J. Classical nucleation theory gives J = A\exp(-\Delta G_{crit}/kT) with a barrier that falls steeply with supersaturation, \Delta G^{*} \propto 1/(\ln S)^{2}; where the induction time is dominated by nucleation, t_{ind} \propto J^{-1}.
Full page in D. Crystallization from solution →The temperature range in which nuclei form at a useful rate; it usually lies below the temperature of fastest growth, and storing outside it helps prevent crystallization.
Full page in Crystallization tendency →Nucleation is the formation of crystal nuclei, the first of two dependent steps of crystallization, each with its own rate and temperature dependence.
Full page in Crystallization tendency →The ratio of drug concentrations in octanol and in an aqueous buffer at equilibrium, given as log P; it measures drug lipophilicity.
Full page in A. Release mechanism and LoC →The fraction of the dose reaching the circulation, F = F_a F_{gut} F_H.
Full page in Bioperformance →Mechanical break-up of drug particles under the stresses of mixing, for example in the dispersive or kneading elements of an extruder; the authors expect it to add defects and dissolution surface, and suggest that defect stress fields may be the sites where breakage starts.
Full page in ASD process →The release of an oral peptide and its permeation enhancer from one dosage form at the same rate, so that the two reach the epithelium together and at the same relative amounts as in the solid.
Full page in Peptide permeability →The change of a polymer's aqueous solubility with pH through ionization of its acidic or basic groups.
Full page in B. Supersaturation from ASD dissolution →The rise of the solubility of an ionizable drug as pH moves toward and past the pKa; for a weak base the total solubility is the free-base solubility times (1 + 10^{\mathrm{p}K_a-\mathrm{pH}}).
Full page in C. Amorphous solubility and LLPS →The precipitation of an ionizable drug when a change of pH makes its neutral, less soluble form exceed the crystalline solubility: a weak base dissolved in the stomach can precipitate at duodenal pH 5–7; the 2014 series also shifted two weak acids to a final pH of 1.9–3.3.
Full page in D. Crystallization from solution →Two-stage dissolution in which the dose dissolves in acid and the pH is raised, creating supersaturation of a weak base.
Full page in Bioperformance →The supersaturation that arises when a weak base dissolved as its ion at low pH meets a higher pH, as on transfer from the stomach to the small intestine, so that its solubility falls by orders of magnitude while the dissolved amount stays.
Full page in D. Crystallization from solution →The change of which of two separated phases is continuous and which forms discrete domains, as their relative amounts change.
Full page in A. Release mechanism and LoC →The lateral size of the drug-rich (or polymer-rich) regions in a phase-separated dispersion.
Full page in Miscibility and drug-polymer interactions →The rate at which a hydrating dispersion undergoes water-induced amorphous–amorphous phase separation, set against the rate at which it dissolves.
Full page in A. Release mechanism and LoC →The shape and connectivity of the drug-rich and polymer-rich phases that form when water separates a drug–polymer dispersion: discrete (circular, separated) drug-rich domains in a continuous polymer-rich phase, bicontinuous structures, or a continuous drug-rich phase with discrete polymer-rich domains.
Full page in A. Release mechanism and LoC →The rapid thermal expansion of a sample where it absorbs a pulsed infrared laser, detected by an AFM tip in contact as the ringdown of the cantilever; the basis of AFM-IR or PTIR. Absorbed energy becomes heat, the expansion makes the cantilever oscillate and the amplitude against wavenumber gives a local spectrum; the contact resonant frequency also shifts with surface stiffness.
Full page in Solid-state methods →The ability of an amorphous drug or dispersion to stay amorphous, and unseparated, during manufacture and storage.
Full page in Crystallization tendency →The pH at which half of an ionizable drug is protonated; two pH units above the pKa a weak base is almost fully un-ionized and two units below almost fully ionized, which set the pH range of the weak-base solubility studies.
Full page in C. Amorphous solubility and LLPS →The lowering of the glass transition temperature of an amorphous drug by absorbed water, taken in these papers as about 10 °C per 1% water.
Full page in C. Amorphous solubility and LLPS →Lowering of the glass transition temperature of a mixture by a component with a lower Tg; in the library water is the usual plasticizer of drugs, polymers and dispersions, and drugs, surfactants and plasticizers lower the Tg of polymers.
Full page in Physical stability →The accumulation of a dissolved polymer at the interface of the drug-rich droplets of a phase-separated solution, where it is thought to reduce droplet coalescence and to disturb heterogeneous nucleation at the droplet–water interface ("likely"); with the cellulosic polymers it is accompanied by some polymer mixing into the droplets.
Full page in D. Crystallization from solution →The attachment of a dissolved polymer to a surface, here the drug crystal (and, for danazol, the droplet interface).
Full page in D. Crystallization from solution →The step in which polymer chains leave the swollen, plasticized gel layer for the medium.
Full page in A. Release mechanism and LoC →The topological constraint between long polymer chains that slows their diffusion.
Full page in A. Release mechanism and LoC →How rigid a polymer backbone is.
Full page in D. Crystallization from solution →The spatial arrangement of a polymer chain in solution and when adsorbed on a crystal: extended or condensed (globular), and, on a surface, trains lying on it, loops bulging into solution and tails.
Full page in D. Crystallization from solution →Dissolution paced by the dissolving polymer, fast and typical of low drug loading, at which the drug can exceed its amorphous solubility and form drug-rich droplets.
Full page in ASD process →The crystallization of the semicrystalline carrier itself, here PEG 3350, as it solidifies from the melt.
Full page in PEG dispersions →The uptake of water by the ionized polymer chains that plasticizes and dilutes them so that they can dissolve.
Full page in A. Release mechanism and LoC →Water affinity of a polymer, judged here by aqueous solubility and by a calculated solubility parameter; the two rank cellulose acetate suberate and HPMCAS differently.
Full page in Bioperformance →The degree to which the acid or base groups of a polymer are ionized at the test pH. The ω-carboxyalkanoate substituents (adipate, suberate, sebacate) of the new cellulose esters have a pKa of about 4.43, so they are nearly fully ionized at pH 6.8 and less than 25% ionized at pH 3.8; the ritonavir and celecoxib in the growth tests are un-ionized at both pH. HPMCAS-LF (pKa 5.5) is taken as nearly fully ionized at pH 6.8 and un-ionized at pH 3; two carboxylated cellulose esters lost their whole effect on telaprevir at pH 3.0; PAA failing for acetaminophen is attributed to its ionization at pH 6.8.
Full page in D. Crystallization from solution →The distribution of a dissolved polymer between the aqueous phase and the drug-rich phase that forms above the amorphous solubility, expressed as the polymer:drug weight ratio in the drug-rich phase or as the partition coefficient K = C_p/C_q (polymer in the drug-rich phase over polymer in water).
Full page in C. Amorphous solubility and LLPS →The idea that a growing drug crystal cannot take a miscible polymer into its lattice and pushes it ahead, so that polymer accumulates at the crystal–amorphous interface and slows drug supply; a related picture holds that growth requires activated drug–polymer demixing at the front.
Full page in Physical stability →Pre-ionizing an acidic dispersion polymer by reacting its acid groups with a base (sodium or an amine) before the dispersion is made.
Full page in A. Release mechanism and LoC →The association of polymer chains with one another in solution, which frees them less to interact with the drug or to adsorb on the crystal.
Full page in D. Crystallization from solution →Association of surfactant molecules with polymer chains in solution, which can raise the solubility of the polymer.
Full page in B. Supersaturation from ASD dissolution →The association of a polymer with a surfactant in solution, which changes the properties of both and, for a hydrophobic polymer, can reduce the polymer's adsorption on the crystal and so its crystallization inhibition.
Full page in D. Crystallization from solution →The uptake of water by the polymer of a dissolving compact, with an increase in volume before the chains dissolve.
Full page in A. Release mechanism and LoC →The ability of a molecule to crystallize in more than one crystal structure; the metastable form often crystallizes first, and recrystallization from the undercooled melt "frequently" gives a metastable polymorph.
Full page in Crystallization tendency →How freely a powder or granule flows, read from its bulk and tapped densities (Carr's compressibility index and Hausner ratio) and its angle of repose; lower indices mean better flow.
Full page in ASD process →A non-random orientation of crystals in a powder, which changes the relative intensity of reflections in PXRD and the total signal in orientation-dependent methods such as SHG. SONICC crystallinity assumes uniformly distributed crystallite orientations and "might not" hold for very sparse early crystals; a habit with a different orientation distribution "could" give a quite different SHG signal for the same polymorph.
Full page in Solid-state methods →Aggregates of solute molecules in solution before a stable nucleus forms; clustering is taken as a prime requirement for crystallization, and if their structure could be tied to the final solid the polymorph "might" be controlled.
Full page in Crystallization tendency →The formation of new crystals from the solution itself, as distinct from secondary nucleation in the presence of crystals; in the acetaminophen study the Crystal 16 induction times were read as primary nucleation and the crystal count after onset as primary plus secondary.
Full page in D. Crystallization from solution →The ratio of the intensity of the first (about 373 nm) to the third (383–384 nm, as printed in different papers) vibronic emission peak of pyrene, which falls as the surroundings become less polar.
Full page in Solid-state methods →Nuclei formed while a melt is cooled faster than the rate that avoids detectable crystallization but slower than the rate that avoids nucleation; they cannot grow before vitrification and remain in the glass.
Full page in Crystallization tendency →The distribution of distances between two groups of atoms averaged over a simulation; in the telaprevir polymer study the peak positions show whether side chains stay extended or fold back.
Full page in D. Crystallization from solution →The mass-weighted spread of the atoms of a molecule around its centre of mass, R_g^2 = \sum m_i(\mathbf{r}_i-\mathbf{r}_{com})^2/\sum m_i; in the telaprevir polymer study a compact, self-aggregated oligomer has a small value.
Full page in D. Crystallization from solution →T_{rg} = \frac{T_g}{T_m} with both temperatures in kelvin.
Full page in Crystallization tendency →The return of a phase-separated amorphous dispersion to one phase once the cause of separation (here sorbed water) is removed and molecular mobility is high enough; below Tg the separated phases stay apart because both are glassy.
Full page in Physical stability →Small amounts of crystalline drug that remain in, or appear soon in, a nominally amorphous sample after preparation.
Full page in Solid-state methods →The overall resistance of a membrane module as the sum of inner boundary layer, membrane and outer boundary layer, 1/K_{in} = 1/k_{in} + 1/k_m + 1/k_{out}.
Full page in Bioperformance →Conversion of laser light into light of twice the frequency (800 → 400 nm; 1064 nm light gives 532 nm) by material that lacks inversion symmetry.
Full page in Solid-state methods →The formation of new crystals in the presence of existing ones, from their surface or from fragments of them, with a lower energy barrier than primary nucleation.
Full page in Bioperformance →Growth of drug on crystals already present in a supersaturated solution, so that no nucleation step is needed.
Full page in B. Supersaturation from ASD dissolution →Phase separation in which drug and polymer go to different phases: an insoluble phase rich in drug and poor in polymer, with the polymer in the aqueous phase; the contrast is associative separation, in which both enrich the insoluble phase (terms cited from polymer solution work).
Full page in A. Release mechanism and LoC →Association of a molecule with its own kind, by hydrogen bonds between drug molecules or between polymer molecules.
Full page in Miscibility and drug-polymer interactions →The thickness over which SHG generated along the beam adds in phase, set by the mismatch of the wave vectors of the fundamental (800 nm) and its harmonic (400 nm).
Full page in Solid-state methods →The size of a band or signal relative to the noise or background around it.
Full page in Solid-state methods →The rule of thumb that a single glass transition, lying between those of the components, shows one amorphous phase, and more than one Tg more than one phase; DSC is called the "golden standard".
Full page in Miscibility and drug-polymer interactions →Two senses occur. In membrane cells the receiver stays far below saturation so that it does not slow transport; in dissolution the medium can dissolve the whole dose (sink index above 1).
Full page in Bioperformance →SI = C_s V/\text{dose}: solubility times medium volume over dose; above 1 the medium can dissolve the dose.
Full page in Bioperformance →Crystallization of an amorphous drug or dispersion during storage or isothermal holding, without dissolution, followed as the rise of the crystalline fraction or as the number and growth of crystals.
Full page in Solid-state methods →The square root of the cohesive energy density, \delta = \sqrt{\sum_i \Delta e_i / \sum_i \Delta v_i} = \sqrt{\Delta E_v / V} in MPa^1/2, estimated by the Fedors group-contribution method from the structural formula alone; a lower value means a more hydrophobic compound, and water is 49.01 MPa^1/2.
Full page in D. Crystallization from solution →The loss of membrane transport that accompanies a rise of apparent solubility when the rise comes from a solubilizer that lowers the free drug and its activity, in contrast to supersaturation from an amorphous formulation, which raises apparent solubility without lowering permeability.
Full page in C. Amorphous solubility and LLPS →Raising the equilibrium (total) solubility by micelles, complexes or proteins, as against raising the activity by supersaturation.
Full page in Bioperformance →Nucleation and growth of crystals from the supersaturated solution, as against crystallization inside the undissolved ASD (matrix crystallization).
Full page in Bioperformance →Conversion of a metastable solid into a more stable one through the solution, in three stages: the metastable phase dissolves to a supersaturated solution, the new phase nucleates driven by that supersaturation, and its growth depletes the solution so that more metastable phase dissolves.
Full page in B. Supersaturation from ASD dissolution →The free energy of transferring a molecule from vacuum into water, calculated here for cellulose side-chain monomers in implicit water; more negative means better solvated.
Full page in D. Crystallization from solution →The surface of a molecule reachable by a water-sized probe (1.4 Å), reported per atom; it shrinks when a chain folds onto itself.
Full page in D. Crystallization from solution →How fast the solvent is removed when an amorphous solid is made from solution; fast removal (spin coating) shortens the time the solution spends supersaturated before it becomes viscous, slow removal lengthens it.
Full page in Crystallization tendency →Kinetic phase separation of a drug–polymer system caused by the changing solvent composition as the solvent leaves, even where the dry components would mix; the system crosses a miscibility gap during drying and the dry glass traps the result.
Full page in ASD process →The smallest separation or feature size at which a method still distinguishes two objects or phases.
Full page in Solid-state methods →The split of total drug into free, micellar, complexed, droplet and crystalline species; only free unionized drug is thought to cross a membrane.
Full page in Bioperformance →The surface area of a powder per gram, here from nitrogen adsorption (BET) at 0.05–0.25 relative pressure.
Full page in ASD process →A local AFM-IR spectrum that contains bands of the neighbouring phase or of material below or beside the probed spot, so that both components appear in both phases even if the phases are fully separated: "some prudency is in order".
Full page in Solid-state methods →Growth of a crystal as a round aggregate of radiating fibres (a spherulite) into the supercooled liquid; its diameter grows linearly with time and the slope is the growth rate.
Full page in Miscibility and drug-polymer interactions →Spontaneous demixing of a solution beyond the spinodal curve, with no nucleation barrier; between the binodal and the spinodal a new liquid phase must nucleate, and the "metastable zone for LLPS" is the distance between them.
Full page in C. Amorphous solubility and LLPS →The mechanism (Cabrera and Vermilyea, outside the library) by which adsorbed impurity molecules hold back an advancing growth step: the step must bulge between adsorbed molecules, its radius of curvature is limited by their spacing, closer spacing means slower growth, and growth stops when the spacing equals twice the critical radius \rho_c of a two-dimensional nucleus; because \rho_c falls as supersaturation rises, the maximum effect of a fixed impurity spacing falls with S. Ilevbare and co-workers chose it among four mechanisms for adsorbed impurities (surfactant action, incorporation, kink blocking, step pinning) by argument, because large polymers adsorb irreversibly.
Full page in D. Crystallization from solution →The blocking of a donor or acceptor group by bulky neighbours, so that it cannot reach a polymer group or a crystal partner.
Full page in Miscibility and drug-polymer interactions →Stabilization of droplets or particles against coalescence by repulsion between adsorbed layers of polymer or surfactant at their surfaces.
Full page in A. Release mechanism and LoC →The relation between the diffusion coefficient of a particle and its hydrodynamic radius, D = k_B T/(6\pi\eta r).
Full page in C. Amorphous solubility and LLPS →The mean time for molecular rearrangement in a glass or supercooled liquid; in this chapter it is calculated with the Adam–Gibbs–Vogel equation from Tg and fictive temperature and compared with crystal growth.
Full page in Physical stability →The approach of a glass toward the equilibrium supercooled liquid, with loss of excess enthalpy and entropy.
Full page in C. Amorphous solubility and LLPS →Nucleation of an amorphous solid in its glassy state, well below Tg, where mobility is low.
Full page in Crystallization tendency →The amorphous state between Tg and Tm: mobile, but below the melting point; below Tg the same material is a glass. "Undercooled melt" is used as a synonym.
Full page in Crystallization tendency →Formulations, such as amorphous solid dispersions, that dissolve to a concentration above the crystalline solubility and therefore need an inhibitor to hold it over the absorption window; the bile-salt papers ask whether surfactants and the bile salts of the test medium help or harm them.
Full page in D. Crystallization from solution →The LLPS (or onset) concentration divided by the equilibrium solubility of the crystalline drug in the same medium.
Full page in C. Amorphous solubility and LLPS →A solution concentration above the crystalline solubility of the drug.
Full page in C. Amorphous solubility and LLPS →The fraction of the adsorption sites on the drug crystal that are occupied by polymer, \theta_{eq} = n_{ad}/n_{max}, from 0 (no polymer) to 1 (all sites occupied); complete coverage is not necessary to stop growth.
Full page in D. Crystallization from solution →Nucleation and growth of crystals at a free surface of an amorphous solid, reported to be faster than in the bulk by orders of magnitude because surface molecules are more mobile.
Full page in Crystallization tendency →A drug-rich layer at the surface of a dispersion or at the dissolving interface.
Full page in ASD process →Faster crystal growth at a free surface of an amorphous solid than in its bulk, thought to reflect higher surface mobility near or below Tg.
Full page in Physical stability →The mobility of molecules at the free surface of an amorphous solid, which is taken to be much higher than in the bulk and to be the reason why crystals nucleate and grow faster at a surface (see surface crystallization).
Full page in ASD process →The release rate of one component of a compact of constant exposed area, per unit area and normalized to the component's weight fraction, so that drug and polymer of a dispersion can be compared with each other and with the neat components; it is the intrinsic dissolution rate per component.
Full page in A. Release mechanism and LoC →The arithmetic mean roughness Ra of an AFM height image (Gwyddion 2.47), used as a single number for whether a spin-coated or cast film is featureless or carries domains.
Full page in ASD process →The uptake of a surfactant into the drug-rich phase, nanodroplets in solution or drug-rich domains in a hydrated dispersion, read from its depletion from the aqueous phase or from its spectral bands in the drug-rich phase.
Full page in A. Release mechanism and LoC →In these papers a pair of additives is "synergistic" when its growth-inhibition ratio exceeds the ratio of each component alone; the paper does not compare the pair with an additive or multiplicative expectation, and the pair carries twice the total polymer of a single-polymer run.
Full page in D. Crystallization from solution →A plot of the liquidus temperature, the temperature at which the last crystal melts, against the composition of a drug–polymer mixture.
Full page in PEG dispersions →A phase diagram of three components.
Full page in ASD process →Crystal growth rate plotted against the distance from each system's own glass transition, T - T_g, so that the part of an additive's effect that comes from shifting Tg is removed and the remainder can be compared.
Full page in Physical stability →Chemical loss of drug or polymer at the temperatures of hot melt extrusion, read as a fall of the HPLC assay and as degradant peaks; amorphous drugs are "more reactive" than crystals, which generally do not degrade much until they melt.
Full page in ASD process →The activity of the drug in a phase, the product of its mole fraction and activity coefficient, a_i = x_i\gamma_i, or of concentration and activity coefficient, a = C\gamma; at phase equilibrium it is equal in all phases.
Full page in C. Amorphous solubility and LLPS →The free-energy difference between the supercooled liquid (amorphous form) and the crystal, written ΔGv per unit volume or ΔG per mole or gram; it is zero at Tm and grows on cooling.
Full page in Crystallization tendency →The line on a ternary phase diagram joining the compositions of two phases in equilibrium; every overall composition on it separates into the same two phases.
Full page in A. Release mechanism and LoC →The span between the melting point and the glass transition, the range a melt must cross to become a glass.
Full page in Crystallization tendency →The formation of a new molecular layer on a crystal face from a small two-dimensional island (or from a spiral step), the way a face grows at low supersaturation; the growth rate then rises roughly with the square of the supersaturation σ, and above a critical supersaturation the island shrinks to a single growth unit, the layers disappear and growth becomes continuous and linear in σ (kinetic roughening).
Full page in D. Crystallization from solution →The aqueous boundary layer next to a membrane or solid surface that adds a diffusion resistance; thinner under flow.
Full page in Bioperformance →The relation d\ln x/dT = \Delta H_f/(R\,T^2) between the temperature dependence of a mole-fraction solubility x and the heat of solution; in the PEG papers it is used to extrapolate the solubility of a drug along its liquidus to 25 °C. This draft covers the solubility use; the evidence table lists a different use of the relation in another subcategory.
Full page in PEG dispersions →A simulated crossover study in a population of virtual subjects; a level passes when the 90% confidence interval of the test-to-reference ratio of Cmax, AUCt and AUC lies within 80.00–125.00%.
Full page in Bioperformance →The factor e^{-I(a_2)} in Eq. 1, the activity of the amorphous drug once it has absorbed water to saturation; it is below 1 because water dilutes the amorphous drug, and lowers the predicted amorphous solubility.
Full page in C. Amorphous solubility and LLPS →Equilibrium water content of a solid against relative humidity (water activity) at fixed temperature; for amorphous solids it can be treated as dissolution of water and fitted with Flory–Huggins theory.
Full page in Physical stability →The uptake of water vapor by an amorphous drug as a function of relative humidity; amorphous solids sorb more than their crystals, and the uptake sets both the activity of the water-saturated amorphous drug and the wet Tg.
Full page in C. Amorphous solubility and LLPS →How readily a medium spreads on a solid.
Full page in ASD process →The electrical potential at the slipping plane of a particle or droplet in liquid; here a read-out of the charge that an adsorbed or ionized polymer gives a drug crystal or a drug-rich droplet.
Full page in D. Crystallization from solution →Demixing of two miscible components caused by a third component, a solvent, that interacts very differently with each of them; the larger the difference between the solvent–component interaction parameters, the stronger the tendency to separate.
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