www.intechopen.com/download/pdf/30914
2nd page
2. Impact of crystal habit on pharmaceutical processing
Drug discovery and characterization relies on the nature of the target molecule and the
relative physicochemical properties of drugs. Identifying all relevant crystal habit of a drug
which is an important variable in pharmaceutical manufacturing at the development phase
from research to commercialization is of substantial value. Due to the different crystal form
variations of some basic physical properties like, solubility, dissolution rate, melting
behavior, and certain micromeritic properties or performance characteristics, e.g. tablet
compressibility, mechanical strength, powder flow provide alternatives to select a form that
presents the suitable balance of critical properties for development into the drug product.
Establishing such modification information at an early stage of drug development process
lessens the risk of process alterations given form changes and brings in the opportunity to
attain more comprehensive rational property coverage.
The merit of changes in crystal surface form and habit of drug powders by recrystallization
method is much more realized when there is an essential to diminish variations in raw
material characteristics, to certify reproducibility of results during drug preformulation, and
also to judge fairly about the cause of poor performance of a dosage form. Besides, the
changes in crystal habit of a drug going together with or without polymorphic
transformation at some point in processing storage could account for serious implications of
physical stability in dosage forms. Thus, it seems underlying to have a deeper insight to the
crystal structures and control the solid-state chemistry of drug substances to design a more
systematic and intellectual pharmaceutical dosage forms.
In a survey carried out by Sinclair et al. ibipinabant a potent and highly selective
cannabinoid receptor antagonist was evaluated for its solid-state physical stability and
recrystallization kinetics in tablet dosage forms using fourier transform raman spectroscopy.
The findings of the study showed that exposure to moisture had notable influence on the
crystallinity of amorphous ibipinabant. The recrystallization kinetics measurements
revealed a two-step process with an induction period (nucleation) followed by rod-like
crystal growth by application of the Johnson–Mehl–Avrami kinetic model. On the whole
their method provided reliable and highly accurate predictive crystallinity assessments after
exposure to a variety of stability storage conditions for ibipinabant (Sinclair et al., 2011).
Recently, Dahlberg et al. analyzed the stability of the amorphous drug, flutamide, by a
combination of localized nuclear magnetic resonance (NMR) spectroscopic and NMR
imaging techniques. Owing to the fact that, NMR relaxation is sensitive to both the
crystalline and amorphous state and the size of the drug substance, it allows for an in situ
monitoring of the state of the drug during tablet disintegration and dissolution periods.
With regard to the results of the NMR experiments, recrystallization was believed to be
related to its enabling factors such as local hydration level and local mobility of the polymer
matrix. Eventually, it was verified that the primarily amorphous flutamide may recrystallize
either by nanoparticle coalescence or by ripening of crystalline particles (Dahlberg et al.,
2011).
The solid-state properties of sulfathiazole and chlorpropamide were modified through
recrystallization using supercritical antisolvent process by Yeo et al. They confirmed that the
operating conditions of the system such as carbon dioxide injection rate, type of solvent, and
temperature significantly had an effect on the physical characteristics of the resulting
crystals. Considering the results of the study, drug crystals processed with supercritical
system exhibited more ordered appearances with clean surfaces and sharp angles compared
with the unprocessed particles where crystal habit changed from tabular to acicular when
the carbon dioxide injection rate increased. Photomicrographs of sulfathiazole crystals with
methanol as a solvent, confirmed a needle-like acicular and a tabular crystal habits in rapid
and slow injections, respectively. Whereas, in the case of chlorpropamide, processed drug
particles in the rapid injection experiment exhibited columnar habit in a regular shape,
while relatively large crystals with sharp angles were observed in the slow injection mode
when acetone was used as the solvent. Overall experimental observations suggested that the
supercritical antisolvent process could provide favorable environment for the solid growth
of a single type of crystalline drug, minimizing the conditions for growth-related
imperfections (Yeo et al., 2003).
According to the fact that thermal analysis has been frequently used to identify crystal forms
of drugs and in the course of thermal analysis, crystal transformation is often observed as
well as melting and decomposition, Suzuki et al. studied mechanisms of thermal crystal
transformation through melting and recrystallization. They characterized two anhydrates
(��-from and ��-from) and two hydrates (hemihydrate and monohydrate) forms of a novel
fluoroquinolone antibiotic, sitafloxacin, in addition to sesquihydrate which is used in the
marketed drug products. The results of crystal structural that were characterized by infrared
spectroscopy, X-ray powder diffractometry and thermal analysis revealed quinolone rings
of sitafloxacin had distorted planar structure and quinolone ring of the drug in ��-form and
monohydrate hold opposite torsion to those in ��-form and sesquihydrate. These kinds of
thermal analysis are often recommended as a routine tool for quality control of thermal
dehydration and subsequent crystal conversion of drugs (Suzuki et al., 2010).
.....
NOTE: THE LAWSUIT vs TEVA incorporates discussion of the crystal type of nuvigil and the recrystallization solvent of choice- scroll to the bottom of the pdf
patentdocs.typepad.com/files/nuvigilorder.pdf
Teva agrees to cooperate in good faith to provide for use in the Litigation, or any action related thereto, reasonable discovery sufficient to show the following:
1.
The identity and properties ofall armodafinil solid forms prepared or studied by or for Teva, including, but not limited to, the polymorphic and solvate forms disclosed in any Cephalon or Teva U.S. or foreign patent or patent application, and the reasons why any research or development by or on behalf of Teva related thereto is or is not ongoing.
2.
The reasons underlying, and bases for, Teva's decision to use the Form I polymorph of armodafinil ("Form I") in its proposed generic armodafinil products under ANDA 200-152, including any analyses conducted by or for Teva relating to the stability or other properties of Form I or comparing Form I with other armodafinil solid forms.
3.
Any disadvantages ofthe armodafinil synthesis or crystallization procedures disclosed in U.S. Patent No. 4,927,855 known to Teva, and the bases therefor, including, but not
Case 1:09-cv-00918-GMS Document 119 Filed 05/11/11 Page 4 of 5 PageID #: 1106
limited to, the basis for Teva's statements in Patent Application Publication No. 2008/0031939 at ~~ 8, 10, 14,36, and alternative methods for making armodafinil developed by or for Teva and the reasons underlying, and bases for, Teva's development of the alternative methodes).
4. The identity and crystal structure measurement of all armodafinil polymorphs obtained by or for Teva when using ethanol (regardless of concentration or grade or purity) as a crystallization solvent.
2
Case 1:09-cv-00918-GMS Document 119 Filed 05/11/11 Page 5 of 5 PageID #: 1107
As you can see this is a stipulation that makes TEVA prove their methodology and their own studies that found the ideal usage of the crystal type, the recrystallization solvent-
ethanol-
as a means to kind of halt them( ex fake data, their lead on this solvent/crystal type could be proved that it came from a cephalon leakage and not their own clinical data, if there is no data or trials of the other types them cephalon wins, but most likely TEVA has covered themselves.)
Now in comparison-MODALERT...
Looking at SUNPHARMA'S patent for modafinil and their derivatives..
http://www.sumobrain.com/patents/wi...lmethylsulfinyl-derivatives/WO2005046854.html
we can see on page 17 where it references its substituents, modafinil is shown as example 1 ( where r1=h) and on page 18...
"The above product is charged in acetone and heated to 50-55 C. DM water is added to the reaction mixture ...... The precipitated product is filtered and washed with acetone water mixture to furnish compound of formula 1 (wherein R1=H)..."(MODAFINIL)
There are 3 other methods but they also incorporate DI water and the last incorporating methanol, notably these are not recrystallization but complex purification technique(which affects crystal formation via solvent used)
So most likely we can conclude absolute ethanol recrystallization is skipped and this other purification technique is used for MODALERT, conflict could be completely evaded with the drug- but im sure the recrystallization/preparation of the new form of it via ethanol is a well kept patented secret. This could be how they evaded patent conflicts because of the final molecule's actually not being the same(size crystal structure).
Apologizes for the rambling block of text but hopefully someone else will attempt this, im actually going to recrystallize a small batch of the modalerts i have in absolute ethanol and report back.. goodluck
