Physicochemical Properties.

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These encompass pH of aqueous solution, melting point, and refractive index. Tests in this category must be figured out by the physical nature of the drug substance and its intended use.

Pwrite-up Size.

For substances to be offered in particular formulations such as solid or suspension commodities, the pwrite-up dimension deserve to have actually a significant effect on dissolution prices, bioavailcapacity, and also stcapacity. A decision tree in the pointer gives guidance regarding when particle size testing must be taken into consideration.

Solid-State Forms.

This section addresses the truth that some drug substances exist in different physical forms such as polymorphs or solvates. Differences in these develops might, in some situations, influence the high quality or performance of the brand-new drug commodities. In instances wright here differences exist that have actually been shown to influence product performance, bioavailcapability, or stability, the appropriate solid state have to be stated. The guideline consists of decision trees, which, once adhered to, sequentially provide guidance on once, and also exactly how, solid-state develops have to be monitored and managed.

Analytical methods frequently offered to inspect for solid-state attributes incorporate melting suggest (consisting of hot-phase microscopy), solid-state infrared spectroscopy, x-ray powder diffractivity, thermal analysis (e.g., differential scanning calorimetry, thermogravimetric evaluation, and differential thermal analysis), Ramale spectroscopy, scanning electron microscopy, and also solid-state nuclear magnetic resonance (NMR).

The sequential decision tree strategy considers whether polymorphism in a drug substance can affect performance of the drug product and leads to a last decision point for determining whether polymorph specifications have to be collection for a drug product.

Tests for New Drug Substances That Are Optically Active.

Chiral impurities had actually been excluded from ICH guidelines on impurities bereason of the practical difficulties of measuring them. However before, in Q6A, a decision tree explains if, and also as soon as, chiral identity tests, impurity tests, and also asclaims may be necessary for both new drug substances and assets, according to criteria such as the following:


Impurities. For single-isomer drug substances, the other enantiomer should be considered the very same as any type of various other impurity.

Assay. An enantioselective determicountry should be part of the specification.

Identity. The identification test must be capable of distinguishing in between a single isomer and also its opposite enantiomer.

Drug product. Control of the various other enantiomer is crucial if it is a deterioration product. Wright here the enantiomer is not a destruction product, an achiral assay might be enough for assay measurement, and an identification test have to be establimelted that is qualified of verifying the presence of the correct enantiomer or racemate, as proper.

Water content. This is essential wright here the new drug substance is well-known to be hygroscopic or degraded by moisture. A particular test such as Karl–Fischer titration is preferred.

Inorganic impurities. The require for these tests should be based upon knowledge of the production procedure. Tests can encompass, for example, sulfated ash/residue on ignition or atomic absorption spectroscopy.

Microbial limits. A decision tree is gave in the guideline to suggest as soon as microbial testing need to be used.


Amino acids are the structure blocks of proteins. In aqueous solutions of pH selection 3–8, amino acids are present in the zwitter ionic develop +NH3CH(X)COOH, wright here X is the amino acid side chain. The bonding is generally via the carboxyl team. The feasible participation of amino nitrogen in coordinating to the metal although controversial, it is possible, in see of the synthesis of many macrocyclic complexes through some containing nitrogen donor atoms. The data on dissociation constants of some amino acid complexes are given in Table 11.7.


R3+Amino acidKD (M)pHTemp. (°C)MethodRef.
LaSarcosine0.253–825NMR<70>
NdAlanine0.2322Potent.<71>
NdAlanine0.154.022NMR<71>
NdHistidine0.504.022NMR<71>
NdSerine0.1022Potent.<71>
NdSerine0.084.022NMR<71>
NdThreonine0.134.022NMR<71>
PrAlanine0.304.6–5.039NMR<72>
PrAmpicillin6.134.0–4.625NMR<73>
EuGlycine0.203.625Partition<74>
EuGlycine0.083.8NMR<75>
EuAlanine0.183.6–4.525Partition<76>
EuAzetidine-2-carboxylate0.284.6–5.037NMR<77>
LuSarcosine0.133–825NMR<70>

Higher complexes of stoichiometries 1:2 and also 1:3 have likewise been reported. It has been argued that at pH values above 7 amino acid: Ln3+ stoichiometry might change from 1:1 to 1:2. It has likewise been argued that paramagnetic lanthanides can be offered in sequencing peptides from their C-termini <78>.

Small peptides containing amino acids found at the Ca2+ binding sites of proteins have been synthesized and studied. N-acetyl-asp created 1:1 complexes through Ln3+ (Ln=Yb, Tm, Er, Ho, Dy) with Kd values in the range 0.15–0.3 mM. The N-acetyl-asp and N-acetyl-Asp-Gly-aspartylamide are associated through the EF Ca2+ binding site of parvalbumin <79>.


Thermolysin is a zinc metallo enzyme which binds Ca2+ ions. It is composed of a single polypeptide chain of M.W. 34 600 containing 316 amino acid residues. Four Ca2+ ions per molecule offer thermal stcapacity to the enzyme. The crystal structure of both Ln3+ substituted and unsubstituted enzyme has been identified <54>.


Ca2+(S1)​​​​​    Ca2+(S2)   }Bound to carboxy1 groups Glu−0177,Asp−185,Glu−180   Ca2+(S3)     singly  bound  Asp−57,Asp−59,C=O of Gul−61+3 Water molecules                   Ca2+(S4)      singly  bound−C=O of Tyr−193, Thr−194, lle−197;OH  of thr−194;                           COO−of Asp−200;2 water molecules. 

Affinity of Eu3+ for sites S1 and also S2 is better than Ca2+ and for sites S3 and S4 Ca2+ binds even more strongly than Eu3+. Ligand also ranges are given in Table 11.8.


LigandDistance (Å)
Ca 1Eu 1Ca 2
Sites S(1) and S(2)
Asp 1853.63.3
2.72.42.4
Glu 1772.12.1
2.62.42.1
Glu 1901.92.1
2.62.62.1
Glu 1872.02.1
Asn 1832.1
Asp 1383.03.3
H2O 12.92.7
H2O 22.9
H2O 32.6
Ca 3Eu 3
Site S(3)
Asp 573.53.6
2.63.0
Asp 592.02.4
3.43.3
Glu 612.63.2
H2O12.32.0
H2O2.11.8
H2O2.11.7
Ca 4Eu 4
Site S(4)
Tyr 1932.52.4
Thr 1941.81.9
2.22.7
Ile 1973.02.9
Asp 2002.52.8
H2O2.52.2
H2O2.21.8
H2O2.8

An independent examine <81> consisted of inserting Tb3+ probe in site(1) and an acceptor Ln3+ ion (Ln = Pr, Nd, Ho or Er) right into sites S(3) and S(4). Energy deliver arisen between S(1) and S(4). Lifetimes of emission from Tb3+ and Eu3+ in H2O and also D2O brought about one water molecule at site(1). Similarly 3.1 and also 4 water molecules at sites S(3) and also S(4) were acquired. These data are consistent with X-ray crystallographic data. A distance of 10.9–11.8 Å in between S(1) and S(4) was calculated and also is cshed to 10.9 Å derived from crystallography.

The “E-F hand” proteins parvalbumin, troponin C, calmodulin, calbindin and oncomodulin have been studied with respect to lanthanide interactions. The crystal framework of parvalbumin <82> consists of six ∼-helical regions labeled as A-F. One Ca2+ ion is bound in the loop joining C and D helices and the second ion in the loop of E-F. Calcium ion is bound to six protein ligands in the CD website. Ca2+ in the EF website is bound to seven protein ligands and also a water molecule.


TABLE 11.9. Dissociation constants of miscellaneous lanthanides for the 2 Ca2+-binding sites of parvalbumin.


Ln3+Kd (M × 10−11)ReferenceCD siteEF site
La3+2.04.8<83>
Ce3+3.24.8<83>
Gd3+5.05.0<83>
0.50.5<84>
Tb3+6002.0<85>
Yb3+524.0<83>
Lu3+364.8<83>

X-ray crystallographic studies present that lanthanides have the right to replace Ca2+ in these proteins isomorphously. The enhance may not be perfect but the perturbations are tiny. In general lanthanides bind to the proteins more strongly than Ca2+ bereason of the greater ionic potential of the lanthanides. It is interesting to note that some enzymes additionally associate through lanthanides although the enzymes carry out not need Ca2+ for their enzymatic task. In this regard, lanthanide substitution gives structural indevelopment and additionally inhibits the activity. Some data for lysozyme and also trypsin are given in Tables 11.10 and also 11.11, respectively.


Ln3+Ka (M−1 × 103)
La3+5.0 ± 1.4
Pr3+7.5 ± 3.7
Nd3+3.7 ± 2.1
Gd3+7.0 ± 2.6
Tb3+4.0 ± 1.7
Dy3+8.7 ± 4.0
Er3+6.6 ± 1.5
Tm3+4.1 ± 1.9

In some proteins like concanavalin A Ln3+ ions do not bind to the Ca2+ site. In some situations steel ions such as Mg2+, Mn2+ and also Fe3+ might be disinserted by lanthanides. Certain proteins prefer lysozyme and concanavalin A have distinctive binding sites which might be inhabited by lanthanides. The association or binding constants of lanthanides via various protein span a large selection. The affinities of lanthanides for proteins boost in general via boost in charge at the binding site and decrease in hydration. The smaller Ln3+ ions cshed to Ca2+ ion size are good candidays for binding proteins.

Lanthanides substitution in proteins additionally provide structural and also sensible facets of proteins. The methods which provide such valuable information are NMR and also luminescence methods. NMR helps assignment of peaks and likewise offers conformational evaluation (i.e.) in identification of acid residues in the vicinity of the binding website. A useful instance arises once the lanthanum binding site is in proximity to the energetic website. Luminescence spectroscopy provides the variety of water molecules bound and also likewise the interionic distance in situations wbelow 2 binding sites are present.

Lanthanides are much better cofactors than Ca2+ for the activation of trypsinogen by trypsin. Proteins favor calmodulin retain their biochemical task even after substitution by a lanthanide. This is because of the exact same level of conformational changes produced by Ca2+ and Ln3+ ions. But most Ca2+ requiring proteins function less successfully on substitution by Ln3+ ions. The function of Ca2+ in the proteins can be elucidated by lanthanide substitution, and also an instance of this is the instance of staphylococcal nuclease.


This was the initially synthetic radionuclide. From that time on many species of radionuclides were developed by bombardment of elements via charged pwrite-ups making use of the assorted types of accelerators. In enhancement, helpful usage of fission power enabled production of an excellent amount of fabricated radionuclides, not just by neutron irradiation created with nuclear reactors however likewise by processing spent fuel.

Nuclear reactions are normally represented as Eqs. (3.1) and (3.2), that is, on the left is the symbol for the target nuclides, the initially symbol in the parentheses suggests the bombarding pshort article (or projectile), the second the emitted particles and the symbol of the product on the appropriate. In the equation, the left side of the comma reflects the mechanism of the reactants and also the appropriate shows the device of the commodities. Before and also after the nuclear reaction, both the amount of mass number and also the sum of atomic number remajor unreadjusted.


When a targain, as a thin film, is exposed to a bombarding ppost (projectile) at the flux (cm2 s− 1) or ϕ for t s, the number of the tarobtain nuclide, N, decreases by the equation of


wright here σ is the amount characterized by the nuclear reactivity in question and the power of the bombarding pwrite-up and also is dubbed cross section which has actually the dimension of cm2. Hence, N0 is N at t = 0.


When the fragmentation constant of the nuclide produced is s− 1, the price of production of the nuclides is expressed as Eq. (3.4):


Even after emitting neutrons, all the fission recoils still have actually too many neutrons compared via the prolots, and have actually a trend in the direction of even more steady nuclei by repeating β− fragmentation. The series associated via β− disintegration is referred to as a fission chain. The final member in the series is a secure nucleus without fail. As an illustration, the fission yield for 235U is presented in Fig. 3.1. The fission yield curve for 235U induced by thermal neutrons has actually a deep valley at the centre compared through that by the 14 MeV neutrons. Since two pieces are created for one fission, the sum of the returns pieces amounts to 200%.



In nuclear reactions, the total momentum of the mechanism is conserved prior to and after a nuclear reaction, and also the product nuclide need to mainly obtain some kinetic power of recoiling at the emission of γ-ray or a particle. When the energy of incident or the ejected particles is > 10 keV, the tarobtain atom may obtain the recoiling energy exceeding the chemical bond energy (several eV) and also consequently the product nuclide is knocked out of the molecule. An atom possessing such a high recoiling power is dubbed a “warm atom” and the field concerned with this type of chemical readjust accompanying nuclear reactions is referred to as “recoil chemistry” or “hot-atom chemisattempt.”


The recoil phenomenon is often watched with (n,γ) reactions which are recognized in regards to the Szilard-Chalmers reaction (1934). Although the capture of a thermal neutron does not administer sufficient power to break a chemical bond, the emission of γ-ray complying with the neutron capture may cause recoiling. The recoiling energy E acquired by a target atom via atomic mass M (in amu) is provided as


For instance, 128I produced by a (n,γ) reaction on ethyl iodide is recoiled and thus, as soon as shaken with water, it is moved into the water phase in carrier-free state (ideally speaking). This is the first example of Szilard-Chalmers reactions which are currently broadly stupassed away and also used for the manufacturing of some isotopes in high certain task.

Tbelow are some special techniques of chemical synthesis recoiling phenomenon (recoil synthesis). For instance, anthracene labelled with 14C is synthesized by irradiating acridine via neutrons with 14N(n,p)14C reactivity. Similarly, 3H labelling is realized with the usage of 3He(n,p)3H or 6Li(n,α)3H. For this objective the compound to be labelled is combined via 4He gas or Li2CO3 and also then irradiated via neutrons.


The recoiling phenomenon is, of course, likewise watched in degeneration procedures. The occurrence of this phenomenon via α-degeneration has been famous because the early on days and also employed as a separation process. It likewise takes location with β−-degeneration, providing various nuclear chemical substances.


The spallation reactivity is an additional instance of one-of-a-kind nuclear reactions, by which many type of nuclides’ reasonably tiny mass number (around 10–20, the smaller the number, the better the yield) in comparikid with the tarobtain nuclide is produced concurrently. The instance is


The actinide facets are the elements with atomic numbers of 90 till 103 being members of a shift series, the first member of which is actinium (Z = 89); 14 electrons are included successively, start formally with thorium (Z = 90) and finishing via lawrencium (Z = 103).


The straightforward way to achieve light actinides is by neutron irradiation of aspects of lower atomic number. For example, the production of Pa has actually been developed by the transmutation of Th through neutron developed in a high-flux nuclear reactor.


The elements Am and also Cm additionally exist in invested fuel. However before, large range production is perdeveloped by neutron irradiation of 239Pu.


The synthesis of transfermium facets past Fm is prospered by nuclear reactions of charged pposts via targets of an actinide element of a reduced atomic number.


The physical and chemical characteristics of actinides are as follows:

In an aqueous solution of pH 3 +, M4 +, MO2+ and also MO22 + corresponding, respectively, to M(III), M(IV), M(V) and also M(VI).

At a low concentration, actinide ions tfinish to undergo hydrolysis. For example, uranium (IV) begins to undergo hydrolysis in aqueous solution above pH > 2.9. As the pH rises, U(IV) inevitably precipitates as hydroxide, U(OH)4. The actinide ions of the (IV) state are specifically prone to hydrolysis and polymerization.

Actinide cations have actually a strong tendency to react via assorted inorganic and organic ions or agents, developing facility ions.


P. Kurzweil, in Encyclopedia of Electrochemical Power Sources, 2009

The pH concept

Søren Paul Lauritz Sørensen (Copenhagen, 1909) characterized the ‘pondus hydogenii’ as the logarithmic meacertain of the acidity of aqueous solutions, pH=−log c(H+).

At the very same time, the term ‘buffer’ ended up being accepted, which had actually been introduced by Auguste Fernbach and L. Hubert (Paris, 1900) in analogy to connected railmeans cars for biochemical devices. Buffer services were supplied by Hans W. Friedenthal, Pal Szily, and also Bruno Fels in the research group of Nernst in Berlin.

The new pH principle encouraged Joel Hildebrand (later Univ. The golden state, 1913) and also Arthur Ames Noyes (MIT) to construct their theory of acid–base titration curves; they were pupils of Nernst and Ostwald, respectively. Niels Bjerrum (Copenhagen, 1914) outlined the state-of-the-art in his book on alkalimetric and also acidimetric titrations.

Wilhelm Böttger (1897) established proton concentrations with the aid of a hydrogen electrode, which Max le Blanc had introduced in 1893. Protoforms of the glass membrane electrode were defined by the physiologist Max Cremer in 1906, and better occurred by Fritz Haber and Zygmunt Klemenciewicz (Karlsruhe, 1909); view Figure 8. In the 1920s, the pH glass electrode establiburned itself based upon the work of W. S. Hughes (1922).

The chinhydron electrode of Einar Biilmann and Hakon Lund (Copenhagen, 1921) has actually seldom been used for pH measurements.

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Since a lot of nonrare earth impurities deserve to coprecipitate via oxalic acid in precipitation of rare earth ions, it is exceptionally challenging to mitigate the impurities, such as iron, nickel, lead, and manganese, in the rare earth oxalate, especially for high-purity assets. In order to develop the fluorescent grade of europium and also yttrium oxides, before oxalic acid is used to precipitate rare earth facet or the aqueous solution of combined rare earth elements is to be used as feed to solvent extraction separation, sulfide precipitation method is commonly used to remove the microamount of heavy metal impurities. The concentration product constants of some sulfides are noted in Table 7.10.


SulfideKspSulfideKspHgSAg2SCu2SCuSPbSSnS2
4.0 × 10− 58CdS8.0 × 10− 27
6.3 × 10− 50SnS1.0 × 10− 25
2.5 × 10− 48NiS2.0 × 10− 24
6.3 × 10− 36ZnS1.6 × 10− 24
1.0 × 10− 28FeS6.3 × 10− 18
2.5 × 10− 27MnS2.5 × 10− 10