Download “A Study on Synthesis And Characterization Of Various Polymorphic

“A STUDY ON SYNTHESIS AND CHARACTERIZATION OF VARIOUS
POLYMORPHIC FORMS OF ORPHENADRINE CITRATE AND
CARBINOXAMINE MALEATE”
Brief Resume of the Intended work:
a) Need of the Study:
The pharmacological activity of the drugs like Orphenadrine Citrate,
Carbinoxamine Maleate etc. are depends upon their polymorphic forms. A particular
polymorph shows more activity than other polymorphs of the same drug. Sometimes
one of the polymorphs of the same drugs shows toxic effects.
In the polymorphism, molecules arrange themselves in two or more different
way in the crystal; either they may be packed differently in the crystal lattice or there
may be difference in the orientation or conformation of the molecules at the lattice
sites.1 Polymorphs differ in bioavailability, solubility, dissolution rate, chemical
stability, physical stability, melting point, color, filterability, density and many other
properties. Different polymorphs of the same molecule having a different solubility
profile, so it can affect drug efficacy, bioavailability and safety.2
It is reported that Famotidine crystallized from different solvents and mixtures
of solvent, was found to exhibit in three crystal forms A, B, and C, depending upon
solvent system used. In which, B form is commercial form and is most stable and
active compared to that of form A and C.3
Based on these findings in the literature, I have planned to synthesize and
characterize various polymorphic forms of Orphenadrine Citrate and Carbinoxamine
Maleate.
Review of Literature
The reviews of various published work related to the subject and objectives of
study have revealed the following.
]
 Polymorphs are basically classified into two types that is enantiotropic (one
polymorph can be reversibly changed into another by varying temperature and
pressure, e.g. Sulfur) or monotropic (one polymorphic form unstable at all
temperature and pressure, e.g. Glyceryl stearates).4
 In the case of molecular solids, polymorphism arises when a given type of molecule
is able to form different crystal structures and it is important to establish the crystal
structures of the different polymorphs, and single-crystal X-ray diffraction techniques
have been used for this purpose.
Different polymorphic forms of a
given molecule can differ significantly in crystal quality and in many cases only one
or a few of the polymorphs yield single crystals that are suitable for investigation by
single-crystal X-ray diffraction.5
 The International Conference on Harmonization (ICH) Q6A guidelines provide
guidance on when and how polymorphic forms should be monitored and controlled.6
 Approximately half of all the drug molecules used in medicine are administered as
salts, whereas polymorphism is encountered in most of the drug substances known in
solid form.7
 Crystallization occurs in two steps: first, crystal nuclei are formed; second, some of
these nuclei grow into larger single crystals. If a system obey Ostwald’s rule of stages,
metastable forms will be obtained first.2
 Crystallization is a multi-step process, which includes nucleation, crystal growth and
Ostwald ripening of the crystals. Nucleation and crystal growth steps together
determine the nature of polymorph.8
 Because, pharmaceuticals are differ in their physical and chemical properties due to
existence of different polymorphs that affects bioavailability. So, this imposed
stringent regulatory requirements on identification and specification of polymorphs
for a particular drugs as a part of QA process.9
 Under appropriate thermodynamic condition, a less stable polymorph may be
converted into more stable polymorph. Rate of conversion of more stable polymorph
is rapid. In these phases the less stable polymorph dissolves, while the more stable
polymorph crystallizes out by in three steps.10
Objective of the Study:
In view of the above facts our objective of study is to undertake:
a) Synthesis and identify the polymorphic forms of Orphendrine Citrate and in
Carbinoxamine Maleate.
b) Characterization of these polymorphs by IR, DSC, SSNMR and XRD.
b) Materials and Method:
Source of Data:
Data will be obtained from internet facilities, literature and related articles from
libraries of Krupanidhi College of Pharmacy, R. L. Fine Chem. Pvt. Ltd., Indian
Institute of Science, Bangalore & Publications and Journals of Medicinal Chemistry.
Data observation and inferences will be collected on the basis of experiments to be
carried out in the course of research in the R & D laboratory of R. L. Fine Chem.
Pvt. Ltd., Bangalore.
Synthesis:
Synthesis of polymorphic modifications of Orphenadrine Citrate and
Carbinoxamine Maleate employing various solvents under various conditions of
temperature and using different techniques of crystallization.
CH3
O
O
N
OH
CH3
CH3
.
O
N
N
O
CH3
CH3
HO
OH
.
HO
O
Cl
Orphenadrine Citrate
Carbinoxamine Maleate
Methods of Characterization:
Characterization of the synthesized compounds will be performed by using modern
analytical techniques like Melting point, Elemental analysis, IR, SSNMR, XRD,
DSC.
Does the study require any investigations of interventions to be conducted on
patients or other human or animals? If so please describe briefly?
No.
Has ethical clearance been obtained from your institute in case of as above?
Not applicable.
c) List of References:
1. Attwood D, Florence AT, Physical pharmacy. London: Pharmaceutical
Press; 2008. p. 3.
2. Llinas A, Goodman JM, Polymorph control-past, present and future. Drug Dis. Today.
2008; 13(5/6):198-9.
3. Mohamad AH, Mutaz SS, Mohammad SS, Naji MN. Int. J. of Pharm 1997 April
28;149(2):227-32.
4.
Fiese EF, Hagen TA. Preformulation. In: Liberman HA, Lachman L. Kang JL.Editors,
Theory and practice of industrial pharmacy. 3rd ed. Bombay: Varghese Publishing
House; 1987. p. 180.
5. Cheung EY, Harris KDM. Structural characterization of industrially relevant
polymorphic materials from powder diffraction data. Org Process Res Dev. 2003 Nov
1;7(6):970-6.
6. International Conference on Harmonization (ICH) Tripartite Guideline, Specification:
Test procedures and acceptance criteria for new drug substances and new drug products:
Chemical substances,1999.
7. Pandey B, Lohray VB, Lohray BB. Importance of polymorphs and salts in the
pharmaceutical industry. ln: Chorghade MS, editor. Drug discovery and development,
New jersey: John Wiley & Sons, 2007.p. 202.
8. Lohani S, Grant DJW. Thermodynamics of polymorphs. ln: Hilfiker R, editor.
Polymorphism in the pharmaceutical industry, 1st ed. Switzerland: Wiley-VCH, 2006.p.
34.
9. Sichi GA, Stephenson RA, Forbes, Reutzel-Edens SM. Adv Drug Deliv Rev 2001;
48:67-90.
10. Grant DJW, Theory and origin of polymorphism. ln: Brittain HG, editor. Polymorphism
in pharmaceutical solids. Switzerland: Marcel Dekker AG; 1999. p. 26.