Mass analyzer

Mass analyzer is a technique used for the separation of the ions according to mass/charge ratio.

Equation for the Mass analyzer:

1. Lorentz force law:
F=Q(E+v*B)

Where
F = force applied to the ion
Q = ion charge
E = electric field
v*B = the vector cross product of the ion velocity and the magnetic field

2. Newton's second law of motion:
F=ma

Where
F = force applied to the ion
m = mass of the ion
a = acceleration

By combining the above two equations, we get:

Q(E+v*B) = ma

=> E+v*B = a(m/Q)

where m/Q denotes mass to charge ratio.

Types of mass analyzers:

There are various types of mass analyzers:

1. Scanning Mass Analyzers

2. TOF - Mass Analyzers

3. Trapped Ion Mass Analyzers

Ion Source

It is a type of an electro-magnetic instrument, primarily used to create charged particles.

It is used in ion implanters, ione engines, mass spectrometersand particle accelerators.

Mass spectrometry

Introduction:
Mass spectrometry is a technique used in analysis.

It is a form of spectrometry in which, usually, high energy electrons are bombarded onto a sample and this produces charged particles of the parent sample; these ions are then focused by electrostatic and magnetic fields to produce a spectrum of the charged fragments which is helpful in establishing the ratio of charged to mass of the particles.

Essential parts:
The design of a mass spectrometer has three essential modules:

1. An ion source:
This transforms the molecules in a sample into ionized fragments.

2. A mass analyzer:
This causes the sorting of the ions by their masses by applying electric and magnetic fields

3. A detector:
This measures the value of some indicator quantity and thus provides data for calculating the abundances of each ion fragment present.

Uses and applications:
The technique has both qualitative and quantitative uses, such as

1. Identifying unknown compounds,
2. Determining the isotopic composition of elements in a compound,
3. Determining the structure of a compound by observing its fragmentation. Its use is there in the identification and structural determination of the flavonoid glycosides. ( Maciej Stobiecki)
4. Quantifying the amount of a compound in a sample,
5. Studying the fundamentals of gas phase ion chemistry
6. Determining other physical, chemical, or biological properties of compounds.

It is now applicable in the field of proteomics. (Christine C. Wu et al.)

References:
Christine C. Wu and John R. Yates III, The application of mass spectrometry to membrane proteomics, Nature Biotechnology 21, 262 - 267

Maciej Stobiecki, 2000, Application of mass spectrometry for identification and structural studies of flavonoid glycosides , Phytochemistry, 54, 237-256

Further reading:
Mass Spectrometry: Principles and Applications by Edmond de Hoffman and Vincent Stroobant

Mass Spectrometry: A Textbook by Jürgen H. Gross

Metabolism

Metabolism is essential for maintaining life by certain chemical reactions. In the result of these reactions and phenomenon, organisms develop ability to grow and reproduce, while maintaining their structures and adopt itself according to the environment.

Types of Metabolism:
There are two types of metabolism:
1. Catabolism:
Catabolism catabolyze or breaks the organic matter and produce heat or energy as a result.

2. Anabolism
Anabolism utilize the energy produced by the catabolism of organic matter.

Factors important in metabolism:
1. Chemicals
Chemicals are important for the metabolic pathways.

2. Enzymes
These enzymes catalyze a reaction involving the chemicals. They make the environment favourable for a reaction to proceed.

Distribution

Distribution in pharmacology is a branch of pharmacokinetics which describes the reversible transfer of drug from one location to another within the body. It is the movement of molecules of drugs from blood into general body (compartments) and peripheral tissues.

The distribution of a drug between tissues is dependent on permeability between tissues (between blood and tissues in particular), blood flow and perfusion rate of the tissue and the ability of the drug to bind plasma proteins and tissue. pH parturition plays a major role as well.

Once a drug enters into systemic circulation by absorption or direct administration, A drug has to be distributed into interstitial and intracellular fluids.

The lipid solubility, pH of compartment, extent of binding with plasma protein and tissue proteins, cardiac output, regional blood flow, capillary permeability are associated for distribution of the drug through tissues.The drug is easily distributed in highly perfused organs like liver, heart, kidney etc in large quantities & in small quantities it is distributed in low perfused organs like muscle, fat, peripheral organs etc. The drug can be moved from the plasma to the tissue until the equilibrium is established (for unbound drug present in plasma).

The volume of distribution (VD) of a drug is a property that quantifies the extent of distribution.

Further reading:
Comparative Pharmacokinetics: Principles, Techniques, and Applications by Jim E. Riviere

Pharmacokinetics : Principles and Applications by Mehdi Boroujerdi

Clinical Pharmacokinetics Handbook by Larry Bauer

Pharmacokinetics

Pharmacokinetics (in Greek: “pharmacon” meaning drug and “kinetikos” meaning putting in motion, the study of time dependency; sometimes abbreviated as “PK”) is a branch of pharmacology dedicated to the determination of the fate of substances administered externally to a living organism. It is the study of what the body does to a drug.
In practice, this discipline is applied mainly to drug substances, though in principle it concerns itself with all manner of compounds ingested or otherwise delivered externally to an organism, such as nutrients, metabolites, hormones, toxins, etc.
Pharmacokinetics is often studied in conjunction with pharmacodynamics.

Pharmacokinetics includes the study of the mechanisms of absorption and distribution of an administered drug, the rate at which a drug action begins and the duration of the effect, the chemical changes of the substance in the body (e.g. by enzymes) and the effects and routes of excretion of the metabolites of the drug.

ADME
Pharmacokinetics is divided into several areas which includes the extent and rate of Absorption, Distribution, Metabolism and Excretion. This is commonly referred to as the ADME scheme. However recent understanding about the drug-body interactions brought about the inclusion of new term Liberation. Now Pharmacokinetics can be better described as LADME.

Liberation is the process of release of drug from the formulation.

Absorption is the process of a substance entering the body.

Distribution is the dispersion or dissemination of substances throughout the fluids and tissues of the body.

Metabolism is the irreversible transformation of parent compounds into daughter metabolites.

Excretion is the elimination of the substances from the body. In rare cases, some drugs irreversibly accumulate in a tissue in the body.

Pharmacokinetics describes how the body affects a specific drug after administration. Pharmacokinetic properties of drugs may be affected by elements such as the site of administration and the concentration in which the drug is administered. These may affect the absorption rate.

AnalysisPharmacokinetic analysis is performed by noncompartmental (model independent) or compartmental methods. Noncompartmental methods estimate the exposure to a drug by estimating the area under the curve of a concentration-time graph. Compartmental methods estimate the concentration-time graph using kinetic models. Compartment-free methods are often more versatile in that they do not assume any specific compartmental model and produce accurate results also acceptable for bioequivalence studies.


Noncompartmental analysis
Noncompartmental PK analysis is highly dependent on estimation of total drug exposure. Total drug exposure is most often estimated by Area Under the Curve methods, with the trapezoidal rule (numerical differential equations) the most common area estimation method. Due to the dependence of the length of 'x' in the trapezoidal rule, the area estimation is highly dependent on the blood/plasma sampling schedule. That is, the closer your time points are, the closer the trapezoids are to the actual shape of the concentration-time curve.

Compartmental analysis
Compartmental PK analysis uses kinetic models to describe and predict the concentration-time curve. PK compartmental models are often similar to kinetic models used in other scientific disciplines such as chemical kinetics and thermodynamics. The advantage of compartmental to some noncompartmental analysis is the ability to predict the concentration at any time. The disadvantage is the difficulty in developing and validating the proper model. Compartment-free modeling based on curve stripping does not suffer this limitation. "PK Solutions" is an easy to use, industry standard software that produces both noncompartmental as well as compartment-free results suitable for research and education. The simplest PK compartmental model is the one-compartmental PK model with IV bolus administration and first-order elimination. The most complex PK models (called PBPK models) rely on the use of physiological information to ease development and validation.

Further reading:
Pharmacokinetics Made Easy by Donald Birkett

Clinical Pharmacokinetics: Concepts and Applications by Malcolm Rowland and Thomas N. Tozer

Applied Pharmacokinetics and Pharmacodynamics: Principles of Therapeutic Drug Monitoring by William E. Evans, Leslie M. Shaw, Jerome J. Schentag and Michael E. Burton

Absorption

In pharmacology (and more specifically pharmacokinetics), absorption is the movement of a drug into the bloodstream.
Absorption involves several phases. First, the drug needs to be administered via some route of administration (oral, via the skin, etc.) and in a specific dosage form such as a tablet, capsule, and so on.
In other situations, such as intravenous therapy, intramuscular injection, enteral nutrition and others, absorption is even more straight-forward and there is less variability in absorption and bioavailability is often near 100%.
Absorption is a primary focus in drug development and medicinal chemistry, since the drug must be absorbed before any medicinal effects can take place. Moreover, the drug's pharmacokinetic profile can be easily and significantly changed by adjusting factors that affect absorption.
The Processes by which the concentration of the drug at any moment and in any region can be determined is done by translocation of drug molecule. The drug is translocated in the body by bulk flow and diffusion. If the drugs chemically differ, still the transfer by bulk flow can occur by the same mechanism but if the drugs are moving by diffusion, it means that their movement is markedly different. The transfer of a drug is highly dependent on its solubility in either lipid or water.
For movement of the drug from the GIT to the system the sink condition is playing a vital role. Sink condition means, the drug is always in circulation due to blood circulation. So, the conc. of drug is not reaching at equilibrium. Thus, the drug can be diffused due to no equilibrium state.
The smaller molecules can move faster than larger ones.

Dissolution
In the most standard situation, a tablet is ingested and passes through the esophagus to the stomach. Because the stomach is an aqueous environment, this is the first place where a tablet will dissolve.
The rate of dissolution is a key target for controlling the duration of a drug's effect, and as such, several dosage forms that contain the same active ingredient may be available, differing only in the rate of dissolution. If a drug is supplied in a form that is not readily dissolved, the drug may be released more gradually over time with a longer duration of action. Having a longer duration of action may improve compliance since the medication will not have to be taken as often. Additionally, slow-release dosage forms may maintain concentrations within an acceptable therapeutic range over a long period of time, as opposed to quick-release dosage forms which may result in sharper peaks and troughs in serum concentrations.
The rate of dissolution is described by the Noyes-Whitney equation as shown below:

Where:
dW/dt is the rate of dissolution.

A is the surface area of the solid.
C is the concentration of the solid in the bulk dissolution medium.
Cs is the concentration of the solid in the diffusion layer surrounding the solid.
D is the diffusion coefficient.
L is the diffusion layer thickness.

As can be inferred by the Noyes-Whitney equation, the rate of dissolution may be modified primarily by altering the surface area of the solid. The surface area may be adjusted by altering the particle size (e.g. micronization). The rate of dissolution may also be altered by choosing a suitable polymorph of a compound. Specifically, cystalline forms dissolve slower than amorphous forms.
Also, coatings on a tablet or a pellet may act a barrier to reduce the rate of dissolution. Coating may also be used to modify where dissolution takes place. For example, enteric coatings may be applied to a drug, so that the coating only dissolves in the basic environment of the intestines. This will prevent release of the drug before reaching the intestines.
Since solutions are already dissolved, they do not need to undergo dissolution before being absorbed.

IonizationThe gastrointestinal tract is lined with epithelial cells. Drugs must pass through these cells in order to be absorbed into the circulatory system. One particular cellular barrier that may prevent absorption of a given drug is the cell membrane. Cell membranes are essentially lipid bilayers which form a semipermeable membrane. Pure lipid bilayers are generally permeable only to small, uncharged solutes. Hence, whether or not a molecule is ionized will affect its absorption, since ionic molecules are considered charged molecules by definition.
The Henderson-Hasselbalch equation offers a way to determine the proportion of a substance that is ionized at a given pH. In the stomach, drugs that are weak acids (such as aspirin) will be present mainly in their non-ionic form, and weak bases will be in their ionic form. Since non-ionic species diffuse more readily through cell membranes, weak acids will have a higher absorption in the highly-acidic stomach.
However, the reverse is true in the basic environment of the intestines-- weak bases (such as caffeine) will diffuse more readily since they will be non-ionic.
This aspect of absorption has been targeted by medicinal chemistry. For example, a suitable analog may be chosen so that the drug is more likely to be in a non-ionic form. Also, prodrugs of a compound may be developed by medicinal chemists-- these chemical variants may be more readily absorbed and then metabolized by the body into the active compound. However, changing the structure of a molecule is less predictable than altering dissolution properties, since changes in chemical structure may affect the pharmacodynamic properties of a drug.

Other factors
factors which affecting bioactivity, resonance, inductive effect, isosterism, bio-isosterism, spatial consideration.

Further reading:
Pharmacokinetics Made Easy, Revised by Donald Birkett

Basic Clinical Pharmacokinetics (Basic Clinical Pharmacokinetics (Winter)) by Michael E. Winter
Applied Clinical Pharmacokinetics by Larry Bauer