Download 6. Danesh A, Chen X, Davies MC, Roberts CJ, Sanders

“A Study on Synthesis And Characterization Of Various Polymorphic Forms Of
Trimipramine Maleate And Clomipramine Hydrochloride”
Brief Resume of the Intended work:
a) Need of the Study:
Polymorphism is the ability of a substance to exist in two or more crystalline forms
that have a different arrangement and/or conformation of molecules in a crystalline
lattice. It has been estimated that a large number of pharmaceuticals exhibit
polymorphism. For example, 70% of barbiturates, 60% of sulfonamides, and 23% of
steroids are believed to exist in different polymorphic forms or "polymorphs". The
pharmacological activity of the drugs like Trimipramine Maleate and Clomipramine
HCl3 (Shows polymorphism) etc. depends on 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.
Polymorphism affects various kinds of physical and chemical properties depending
on the nature and stability of crystal lattice. Some of these properties of polymorphs
relevant to the pharmaceutical industry are solubility, dissolution rate, bioavailability,
chemical and physical stability, melting point, bulk density, electrostatic properties, flow
properties etc. A number of drugs have shown considerable difference in their physical
properties due to change in their crystalline structure or polymorphic properties1.
Naturally, the difference in solubility can affect drug efficacy, bioavailability and safety1.
It is reported that because of alteration in process and storage conditions, one polymorph
of chloramphenicol-3-palmitate can have an eight fold-higher bioactivity than another,
creating a danger of fatal doses when the unwanted polymorph is administered
unwittingly3.
Moreover, the inadvertent production of an undesired polymorph (or pseudopolymorph), or the spontaneous transformation from the desired crystalline form to an
undesired form, can result in crystalline forms of a drug that are less effective or even
toxic. Thus, the existence and control of polymorphism and pseudo-polymorphism can
be the biggest challenge to obtaining a drug product of constant quality
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. This issue of salts and polymorphs are at the center of new drug discovery,
chemical process, development, analytical chemistry, pharmaceutical sciences,
pharmacokinetics, toxicity and clinical studies, and these issues are encountered
repeatedly by pharmaceutical companies.
Another important issue regarding polymorphism and pseudo-polymorphism is
that there can be considerable regulatory hurdles for a drug that exists in various
crystalline forms. The FDA's regulatory guidelines emphasize control of crystal form and
the use of appropriate techniques to detect and characterize different forms of a drug.
Because of the above issues and findings, It has prompted me to synthesize and
characterize various polymorphs of Trimipramine and Clomipramine.
Review of Literature:
The review of various published works related to the subject and objective of study has
revealed the following:
 Bokra, reported number of drugs show considerable difference in their physical
properties due to change in their crystalline structure or polymorphic properties.
Difference in solubility of polymorph can affect drug efficacy, bioavailability and safety.
And compiles 200 drugs showing polymorphism1
 BP 2009, It is reported that Clomipramine HCl shows polymorphism2
 Haleblian, reported that approximately half of the drug molecules used in medicine are
administered as salts, whereas polymorphism is encountered in most of the drug
substance known in solid form3
 Katriona Knapman has described that single crystal X-ray diffraction is the traditional
method of identifying polymorphs. But, it is often impossible to grow single crystal of
the required size and purity for this method. However recent developments in
computational chemistry allow the prediction of possible polymorphic forms based only
on the molecular structure of the drug. The Polymorph predictor from Molecular
simulations, Inc., is currently the only commercial software package that can predict
possible polymorphs of an organic compound from its molecular structure4
 Kenneth D. M. Harris and Eugene Y. Cheung talked about structural characterization of
industrially relevant polymorphic materials from powder X-ray diffraction data. They
also talked about different technique to determine the crystal structure from diffraction
data i.e., Rietveld profile refinement technique and unit cell determination technique.
They also gave detail about Traditional approach and direct space approach to determine
solution structure of crystal5
 Atomic force microscopy is novel technique to differentiate and characterize polymorphs
of a single drug. Polymorphs of cimetidine has been differentiated using atomic force
microscopy6
 M. Blanco, J. Coello, H. Iturriaga, S. Maspoch and C. Pérez-Maseda have Characterized
and determined crystalline and amorphous forms of antibiotic miokamycin by near
infrared spectrometry7
 Polymorphic purity of ranitidine HCl has been determined and analyzed by diffuse
reflectance infrared Fourier transform spectroscopy (DRIFTS) and X-ray powder
diffractrometry (XRPD)8
 Sarah L. Price, explained about computational predictions of crystal structures and
polymorphic structures of a drug9
 High- Throughput crystallization techniques has been developed that permits rapid and
more comprehensive exploration of solid form diversity with only small amounts (>1mg
per trial) of API. Such systems also facilitate evaluation of the utility of all possible
physical forms of the optimal solid form, thus can accelerate the development process
while minimizing the risk of downstream form related manufacturing and performance
issues. This technique has been employed for elucidation of possible polymorphs of
Ritonavir- anti viral drug10
 Sometimes conversion of unstable (Active) metastable to stable polymorph makes drug
less soluble. Capillary precipitation is the technique that employs supersaturated solution
in small capillary and controls crystallization. Capillary precipitation is experimented on
a highly polymorphic organic compound, resultant crystals displayed a range of
metastable forms11
 Pharmaceuticals may exist in various solid forms featuring different physical and
chemical properties. Probable difference in the bioavailibility of these polymorphic
forms has provoked impositions of stringent regulatory requirements on identification
and specification of polymorphs for a particular drug substance as a part of the quality
assurance process12
 International conference on harmonization (ICH) Q6A guidelines provides guidance on
when and how polymorphic forms should be monitored and controlled.13
 For stability concerns the most stable form is normally employed in the formulations.
However, the metastable polymorphic form may be inadvertently generated due to stress
produced by temperature, mechanical treatment and moisture during processing or
storage of the drug product.14
 Contamination by polymorphic impurities can adversely influence both the stability and
performance of the final product. It has thus become imperative to develop accurate
quantification methods for such low level physical impurities of separate crystalline
phase, in pharmaceuticals14
Objective of the Study:
In view of the above facts our objective of study is to undertake:
A. Synthesize and identify the polymorphic forms of Trimipramine Maleate and
Clomipramine Hydrochloride.
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.
Laboratories Pvt. Ltd., Bangalore.
Synthesis:
Polymorphic forms of Trimipramine Maleate and Clomipramine HCl will be synthesized
by employing various solvents and mixture of solvents under various conditions of
temperature and using different techniques of crystallization.
Structures of these compounds are:
Trimipramine Maleate
N
OH
CH3
O
HO
N
CH3
O
H3C
3-(10,11-dihydro-5H-dibenzo[b,f]azepin-5-yl)-N,N,2-trimethylpropan-1-amine (2Z)-but-2-enedioic acid
Clomipramine Hydrochloride
N
Cl
N
H 3C
CH3
.HCl
3-(3-chloro-10,11-dihydro-5H-dibenzo[b,f]azepin-5-yl)-N,N-dimethylpropan-1-amine
Methods of Characterization:
Characterization of synthesized compounds will be performed by using modern
analytical methods like Melting Point, IR spectroscopy, NMR Spectroscopy, Deferential
Scanning Calorimeter, X- Ray crystallographic Studies.
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
b) List of References:
1. Bokra L. Pharmeuropa 1995;7(4):574.
2. Medicines and healthcare product regulatory agency. British Pharmacopoeia 2009.
Volume I. London: The Stationary Office; 2008. Monographs; p. 525.
3. Haleblian J, McCrone W. Pharmaceutical applications of polymorphism. J Pharm Sci
1969 Aug ;58(8):911-29.
4. Katriona Knapman. Polymorphic predictions – Understanding the nature of crystalline
compounds can be criticalin drug development and manufacture. Mod Drug Dis
2003;3(2):53-7.
5. Harris KDM, Cheung EY. Structural characterization of industrially relevant
polymorphic materials from powder diffraction data. Org Process Res Dev 2003 Nov
1;7(6):970-6.
6. Danesh A, Chen X, Davies MC, Roberts CJ, Sanders GHW, Tenler SJB et al.
Polymorphic discrimination using atomic force microscopy: distinguishing between two
polymorphs of the drug cimetidine. Langmuir 2000;16(2):866-70.
7. Blanco M, Coello J, Iturriaga H, Maspoch S, Perez-Maseda C. Determination of
polymerphic purity by near infrared spectrometry. Anal Chim Acta 2000 Feb 29;407(12):247-54.
8. Agatonovic-kustrin S, Rades T, Wu V, Saville D, Tucker IG.Determination of
polymorphic forms of ranitidine Hcl by DRIFT and XRPD. J Pharm Biomed Anal 2001
Jul;25(5-6):741-50.
9. Sarah LP. The computational prediction of pharmaceutical crystal structures and
polymorphism. Adv Drug Deliv Rev 2004 Feb 23;56(3):301-19.
10. Morissette SL, Stephen S, douglas L, Michael JC, Allmarsson O. Elucidation of crystal
form diversity of the HIV protease inhibitor Ritonavir by High-throughput
crystallization. Proc Natl Acad Sci U S A 2003 Mar 4;100(5):2180-4.
11. Kenneth RM, Jon LH, Caesar ER, Matthew JK, Jeff ST, Joseph GS. Capillary
precipitation of a highly polymorphic organic compound. Crystal Growth Des 2003 Aug
13;3(6):921-6.
12. Sichi GA, Stephenson RA, Forbes, Reutzel-Edens SM. Characterization of the solid state:
quantitative issues. Adv Drug Deliv 2001May 16;48(1):67-90.
13. International conference on Harmonization (ICH) Harmonized Tripartite Guideline,
Specifications: Test procedures and acceptance criteria for new substances and new drug
products: Chemical substances, 1999.
14. Vippagunta SR, Brittain HG, David JWG. Crystalline solids. Adv Drug Deliv 2001 May
16;48(1):3-26.