A seminar on applications of various analytical technique

Prepared By:
Mr. PARTH
M. Pharm, Sem –II
Q. A. Department-SJTPC

Guided By:
Mrs. Parula B. Patel
Head of Q. A. Department-SJTPC, Rajkot
. . 1

1. Introductions
2. Overall industrial Program
3. Need for a Preformulation Study
4. Preformulation Study in Support of New Drug Product Development
5. Stages of Preformulation Studies
6. Preformulation Report
7. Analytical techniques and instruments for preformulation studies
8. Regulatory requirements for preformulation
9. Appendix 1: physicochemical properties and analytical testing for drug
substance
10. Appendix 2: data for supporting development of solid dosage forms
11. Appendix 3: support for quality control and finished product
manufacturing
12. Questions asked in GTU
13. Reference

by A. R. Parmar-SJTPC, Rajkot 21 January 2013 2

 Definition: “Preformulation study is define as the process of
optimizing the delivery of drug through determinations of
physicochemical properties of the new compound that could
affect drug performance and development of an efficacious,
stable and safe dosage form.”

 Preformulation is the study of the chemical and physical
properties of the drug components prior to the compounding
process of the formulation.

 The purpose of the study is to understand the nature and
characteristics of each component and to optimize conditions
of the dosage form manufacture.


 Goal:

i. Establish the identity and physico - chemical parameters of a
new drug substance.

ii. Establish its kinetic rate profile.

iii. Establish its physical characteristics.

iv. Establish its compatibility with common excipients.


 The birth of new drug substance and its eventual marketing
following events take place between the birth of a new drug
substance and its eventual marketing;

i. The drug is synthesized and tested in a pharmacological
screen.

ii. The drug is found sufficiently interesting to warrant further
study.

iii. Sufficient quantity is synthesized to
a) Perform initial toxicity studies.
b) Do initial analytical work and
c) Do initial preformulation.

iv. Once pass initial toxicity phase I (Clinical pharmacology)
begins and there is a need for actual formulations (although
the dose level may not yet be determined).

v. Phase II and Phase III clinical testing then begins and during
this phase the formula is finalized.

vi. After completion of the above, an NDA (New Drug
Application) is submitted.

vii. After approval of the NDA, Production can start (Product
launch).


1. Establishment of drug specifications intended for
toxicological evaluation and clinical supply preparations.
2. Formulation of clinical supplies and establishment of their
preliminary specifications
3. Providing scientific data to support dosage form development
and evaluation of product efficacy, quality, stability, and
bioavailability
4. Evaluation of the stability of early developed dosage forms
5. Fulfillment of the requirement of the CMC section of the
IND and subsequent NDA or ANDA


 A typical development track activity for preformulation
monitoring may be divided into several phases, as discussed in
the following.

1. Selection of a Drug Substance for Dosage Form
Development:

a) Structure Modifications
 In many instances, modification of the chemical structure or
physical property may prove to optimize the therapeutic and
pharmaceutical values of the candidate.


b) Purity
 The purity profile must be established, and quality consistency
must be enforced.

c) Chirality
 Chirality is the existence of different configurations of a
substance with an identical chemical structure.

 This substance may be resolved into enantiomers with
nonsuperimposable mirror images.

 In addition to physiological activities, stereospecificity
influences the physicochemical properties of drugs.


d) Salt Forms Selection
 Many synthetic substances to be used in solid dosage form are
too limited in solubility to be therapeutically effective.

 The desirable solubility for an oral solid is suggested to be more
than 1 mg/ml (0.1%).

e) Prodrugs
 For example, the solubility and dissolution rate of the n-
hydroxymethyl derivative of lomefloxacin is higher than those
of the parent compound, and it can be converted readily back to
the original molecule.

 Commonly used Prodrugs are procaine penicillin metronidazole
phosphate and chloramphenicol sodium succinate.


f) Metabolites
 The metabolism study of a drug candidate should be carried out in
the earlier stage of development soon after the selection process.
 The major metabolites should be tested pharmacologically and
toxicologically against the candidate.
 If similar profiles are found, consideration should be given to
replacing the original drug candidate with its metabolite.

2. Intellectual Property Protection and Patent Filing

3. Selection of Analytical Technique and Development


4. Preparation and Submission of IND

5. Clinical Trial Studies

6. Development and Manufacturing of Dosage Forms

7. Establishment of a QA/QC System

8. Preparation of a New Drug Application

9. Abbreviated New Drug Application


 The preformulation is performed in several stages with
different development cycles, which are discussed in the
following.

a) Preformulation Report, Part 1: Physicochemical Properties
and Analytical Testing for Drugs

b) Preformulation Report, Part 2: Data Supporting the
Development of Dosage Forms

c) Preformulation Report, Part 3: Support for Quality Control
and Finished Product Manufacturing


1. Analytical Profiles (Required for Analytical Method
Development)
a) Identification of Drug Substance
b) Purity
c) Absolute Purity

2. Chemical Properties

3. Thermodynamic and Physicochemical Properties
a) Dissociation Constant, pKa
b) Solubility
c) Method of Solubility Determination
d) Solubilization

4. Pharmaceutical and Mechanical Properties
a) Hygroscopicity and Moisture Absorption/Desorption
b) Powder Characteristics
c) Mixing and Blend Uniformity

5. Solid-State Characteristics
a) Polymorphism
b) Hydrates and Solvates (Pseudomorphism)
c) Amorphous Powders
d) Morphology, Size, and Surface Area


6. Biopharmaceutical Properties
a) Partition Coefficient
b) Permeability in the GI Tract
c) Dissolution Rate and its in vivo–in vitro Correlation

7. Excipient Compatibility Studies

8. Stability


 A preformulation study is performed to gain insight from
physicochemical and biological data into the design and
development of dosage forms.

 Samples are taken in each study and analyzed qualitatively
and/or quantitatively, according to the need.

 Analytical techniques are generally divided into two prevalent
areas in the specific detection and separation sciences.


1. Specific Detection

 Specific detection is an analytical determination based on
specific responses related to the chemical characteristics of a
molecule excited by a certain type of irradiation.

 In this detection method, measurement of the molecule of
interest may usually be performed without separation from
matrix materials or from other ingredients if appropriate
instrumental adjustments are made.

 Techniques such as Fourier transform IR (FTIR), attenuated
total reflectance (ATR), NIR, Raman spectroscopy are used
with increased regularity.


 The detection of foreign metal contaminants is essential with
inductively coupled plasma spectroscopy (ICP), atomic
absorption (AA), and X-ray fluorescence.

 Also notable is the increased attention to analysis of chiral
compounds, as in the synthesis of drug substances. Optical
rotation, ORD, and CD are currently the preferred instruments
for this practice.


 The analytical techniques commonly used in the
preformulation study are:
a) UV Spectroscopy
 UV absorptions are mainly electronic in nature and are
associated with resonating structures in the molecule.

 The UV quantitative determination, generally performed in
solution, is based on the Beer–Lambert law.

 In a preformulation study, solubility, dissolution rate, and some
stability studies (when degradation products have a different
absorption maximum from the parent compound) are performed
with the UV technique.

b) Visible Photometry and Colorimetry

c) IR Spectroscopy

 IR spectroscopy is used extensively in pharmaceutical analysis
for fingerprint identification of a drug molecule and the proof of
its structure.

 IR absorption bands are characteristic of the functional group of
a molecule as well as the structure configuration.

 The wavelength of the IR spectrum is 750–2500 μm.

 The sampling preparation techniques for IR determination are
solution, drug dispersion in a KBr pellet, Nujol mulls, and direct
determination by microscopic ATR preparation.

 An example of modern IR equipment is FTIR, which gives
better quality determination.


d) Raman Spectroscopy

 Raman spectroscopy is based on the phenomenon of inelastic
light scattering.

 When a particle is irradiated at a certain frequency, radiation
scattered by the molecule contains photons of the same
frequency as the incident radiation and may contain photons
(weak signal) with a changed or shifted frequency.

 Raman spectroscopy is a nondestructive tool and requires little
or no sample preparation.

 A sample may be analyzed in solid or powder form or in an
aqueous solution and placed in glass containers such as an
NMR tube, GC vial, test tube, light-path cell, or glass bottle.

 Aside from structure elucidation and functional group analysis,
FT-Raman may be used for quantitative determination of
polymorphs in a preformulation study.

e) NIR Spectroscopy

 NIR is making significant progress through recent advances in
pharmaceutical analysis.
 The advantage of this technique is the rapidity of analytical
determinations without sample preparation and the use of
solvent.
 The NIR spectrum is primarily related to the overtone variation.
Hence, the absorption bands are generally weaker than those in
the IR.
 The wavelength of the NIR spectrum is defined as 2500–3000
μm.
 The detection method is nondestructive.
 Therefore, it is suitable for use in on-line monitoring and meets
100% inspection requirements in quality control practice.


f) X-Ray Diffraction

 The X-ray diffractometry technique obtains information on
substance structure at the atomic level.

 This technique allows measurement of both crystalline and
noncrystalline materials.

 The analysis is nondestructive in nature and handles samples in
the form of powders, solids, and liquids.

 The X-ray diffraction of a single crystal is employed for the
determination of the absolute chemical structure.

 Quantitative ratios of two polymorphs and their percentage of
crystallinity may also be determined.


g) NMR Spectroscopy

 NMR involves the absorption of electromagnetic radiation in
the radiofrequency of a longer wavelength spectrum.

 When a sample is placed with atomic nuclei of hydrogen (1H,
protons), fluorine (15F), or phosphorous (31P) in a magnetic
field, absorption of energy will occur.

 The nuclei shift from the preferred orientation with lowest
energy to a less preferred, high-energy orientation at a
particular frequency.

 Thus a plot of frequency versus intensity of radiation results in
the NMR spectrum of a material.

 Spectra of NMR can be obtained in liquids or in solids.

h) Mass Spectrometry

i) Metal Analysis

 X-Ray Fluorescence

 Atomic Absorption


a) Thin-Layer Chromatography

b) High-Pressure Liquid Chromatography

c) Capillary Electrophoresis

d) Gas Chromatography

e) Ion Chromatography

f) Supercritical Fluid Chromatography


 Equipment for thermal analysis is used extensively for the
preformulation study.
 As in the solid-state investigation, interest is focused not only
on the chemical change but also on the physical change, which
can be illustrated appropriately by thermometric methods.

a) Differential Scanning Calorimetry
b) Hot Stage Microscopy
c) Thermal Gravimetric Analysis
d) Solution Calorimetry


1. Regulatory Compliance

 FDA initiatives and other government regulations influence
pharmaceutical manufacturing operations, including
preformulation studies and quality control systems.

 These regulatory issues include the topics outlined below:


a) Current Good Manufacturing Practices

 The cGMP is an FDA mandatory quality program designed to
ensure that pharmaceutical products are consistently produced
and controlled according to the quality standards appropriate to
their intended use.

 The cGMP was originally developed for the dosage form or
finished product and for bulk drug substances in the absence of
a published guideline.


b) Good Laboratory Practice
 In contrast to cGMP, which regulates manufacturing and its
related quality control activities, good laboratory practice
(GLP) covers research activities.

 The most significant difference between the two sets of
guidelines is in the requirements of archiving for test samples
and data.

 GLP regulates all nonclinical studies and was originally
intended for toxicity testing only.

 The requirements of analytical measurements and methods in
support of toxicological studies are included in the GLP

c) International Conference on Harmonization

 The ICH is intended to avoid duplication efforts for product
registration and manufacturing in world trade.

2. Quality Control for a Preformulation Study

a) Personnel Qualification and Training

a) Analytical Method Validation

a) Documentation and Standard Operating Procedures


1. Explain preformulation study. Give its importance. Describe
thermodynamic and physicochemical properties in
preformulation study. ( 8 marks ) - 2010

2. Give brief review of analytical methods used in
preformulation study. ( 8 marks ) - 2010


1. Dr. Javed Ali, Dr. R. K. Khar, Dr. Alka Ahuja, Dosage form
design, 5th edition, Page no. 01 – 30.

2. Satinder Ahuja and Stephen Scypinski, Handbook of
Modern Pharmaceutical Analysis, Vol. 3, Page no, 172 – 233.


.


A seminar on applications of various analytical technique

A seminar on applications of various analytical technique

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