Profiles of Drug Substances, Excipients and Related Methodology 36

385 Pages·2011·15.76 MB·English

by  Harry G. Brittain (Eds.)

CONTRIBUTING EDITOR
ABDULLAH A. AL-BADR
GUNAWAN INDRAYANTO
FOUNDING
EDITOR
KLAUS FLOREY
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PREFACE TO VOLUME 36
The comprehensive profiling of drug substances and pharmaceutical
excipients as to their physical and analytical characteristics remains
essentialtoallphasesofpharmaceuticaldevelopment,andsuchprofiles
are of immeasurable importance to workers in the field. Consequently,
thecompilationandpublicationofcomprehensivesummariesofphysical
andchemicaldata,analyticalmethods,routesofcompoundpreparation,
degradationpathways,usesandapplications,etc.,havealwaysbeenand
willcontinuetobeavitalfunctiontobothacademiaandindustry.
As the science of pharmaceutics grows and matures, the need for
information similarly expands along new fronts, and this growth causes
an equivalent growth in the repository sources where investigators find
the information they need. The content of the Profiles series continues to
respondandexpandtomeetthisneed,andsochaptersarepublishedthat
fallintooneormoreofthefollowingmaincategories:
1. Comprehensiveprofilesofadrugsubstanceorexcipient
2. Physicalcharacterizationofadrugsubstanceorexcipient
3. Analyticalmethodsforadrugsubstanceorexcipient
4. Detailed discussions of the clinical uses, pharmacology, pharmaco-
kinetics,safety,ortoxicityofadrugsubstanceorexcipient
5. Reviews of methodology useful for the characterization of drug
substancesorexcipients
6. Annualreviewsofareasofimportancetopharmaceuticalscientists
The current volume contains profiles on Buclizine, Chitin, Ezetimibe,
Gemfloxacin,Glimepiride,Lornoxicam,MagnesiumSilicate,andTadalafil.
Thevolumealsocontainsachapterreviewingthedirectcrystallizationof
enantiomers and dissociable diastereomers and a review of the literature
published during 2009 that pertains to cocrystal systems having pharma-
ceuticalinterest.
Asalways,Iwelcomecommunicationsfromanyoneinthepharmaceu-
ticalcommunitywhomightwanttoprovideanopinionoracontribution.
HarryG.Brittain
Editor,ProfilesofDrugSubstances,
Excipients,andRelatedMethodology
[email protected]
ix
1
CHAPTER
Buclizine
Gamal A.E. Mostafa and Abdullah A. Al-Badr
Contents 1. Description 2
1.1. Nomenclature 2
1.1.1. Systematicalchemicalnames 2
1.1.2. Nonproprietarynames 2
1.1.3. Proprietarynames 2
1.2. Formulae 2
1.2.1. Empiricalformula,molecularweight,
andCASnumber 3
1.2.2. Structuralformula 3
1.3. Elementalanalysis 3
1.4. Appearance 3
2. UsesandApplication 3
3. MethodsofPreparation 4
4. PhysicalCharacteristics 6
4.1. Solubility 6
4.2. Meltingrange 6
4.3. X-raypowderdiffractionpattern 6
4.4. Spectralproperties 7
4.4.1. UV/VISspectroscopy 7
4.4.2. Infraredspectrum 7
4.4.3. Nuclearmagneticresonance
spectrometry 7
4.5. Massspectrometry 11
DepartmentofPharmaceuticalChemistry,CollegeofPharmacy,KingSaudUniversity,Riyadh,Kingdomof
SaudiArabia
ProfilesofDrugSubstances,Excipients,andRelatedMethodology,Volume36 # ElsevierInc.
ISSN1871-5125 Allrightsreserved.
1
2 GamalA.E.MostafaandAbdullahA.Al-Badr
5. MethodsofAnalysis 12
5.1. Compendialmethods 12
5.1.1. Britishpharmacopoeiamethods[11] 12
5.2. Spectrophotometricmethods 16
5.3. Potentiometricmethods 18
5.4. Chromatographicmethods 20
5.4.1. Thinlayerchromatography 20
5.4.2. Gaschromatography 28
5.4.3. High-performanceliquidchromatography 28
6. Stability 32
Acknowledgment 32
References 32
1. DESCRIPTION
1.1. Nomenclature
1.1.1. Systematical chemical names
1-[(4-chorophenyl)phenylmethyl]-4-[(4-tert-butylphenyl)methyl]
piperazine;
1-(p-tert-butylbenzyl)-4-(p-chloro-a-phenylbenzyl)piperazine;
1-(p-chlorobenzhydryl)-4-(p-tert-butylbenzyl)diethylenediamine;
1-(p-tert-butylbenzyl)-4-(p-chlorodiphenylmethyl)piperazine;
(RS)-1-(4-tert-butylbenzyl)-4-(4-chlorobenzhydryl)piperazine
dihydrochloride;
Piperazine, 1[(4-chlorophenyl)phenylmethyl]-4-[[4-(1,1-dimethylethyl)
phenyl]methyl];
1-(p-chlorobenzhydryl)-4-(4-tert-butylbenzyl)-hexahydropyrazine;
1-[(4-chlorophenyl)phenylmethyl]-4-[(4-tert-butylphenyl)-methyl]
piperazidine[1–6].
1.1.2. Nonproprietary names
Buclizine;Histabutyzine;Histabutizine;NSC-25141;UCB4445
1.1.3. Proprietary names
Aphilan, Bucladin-S, Buclifen, Buclina, Longifene, Posdel, Postadoxine,
PostafenPostafeno,Softran,Vibazine[1–6].
Buclizine 3
1.2. Formulae
1.2.1. Empirical formula, molecular weight, and CAS number
Buclizine C H ClN 433.0 82-95-1
28 33 2
Buclizine(cid:1)2HCl C H Cl N 506.0 129-74-8
28 35 3 2
1.2.2. Structural formula
Cl
CH
3
CH N N CH C CH
2 3
CH
3
1.3. Elemental analysis
(cid:3)
Buclizine:C77.66%,H7.68%,Cl8.19%,N6.47%[1].
(cid:3)
BuclizineHCl:C66.47%,H6.97%,Cl21.02%,N5.54%[1].
1.4. Appearance
A white or slightly yellowish, crystalline powder, odorless and
tasteless[5,6].
2. USES AND APPLICATION
Buclizine hydrochloride, a piperazine derivative, is a sedating antihista-
minewithantimuscarinicandmoderatesedativeaction.Thedrugisused
mainly for its antiemetic action, particularly in the prevention of motion
sickness,andinthetreatmentofmigraineincombinationwithanalgesics.
Insomecountries,itisgiveninthemanagementofallergicconditionsand
in the pruritic skin disorders. Buclizine has also been used in the treat-
ment ofvertigoassociated withdisordersofvestibular system,although
itsvalueintheseconditionsremainstobeestablished[2–6].
4 GamalA.E.MostafaandAbdullahA.Al-Badr
To prevent motion sickness, the drug is given at least 30 min before
travelling in a dose of 50 mg by mouth which may be repeated,
if necessary, after 4–6 h. The usual dose to alleviate nausea is 50 mg
given up to three times daily. In the treatment of migraine, the drug is
given in usual doses of 12.5 mg at the start of an attack or when one is
known to be imminent. In pruritic skin disorders, the usual dose of
buclizinehydrochlorideis25–50mgdaily[2–5].Thedrughasanantihis-
taminic [2], antimycobactrium [3], anticonvulsant [4], and motion sick-
nesspreventionactivities[5].
3. METHODS OF PREPARATION
Morren and Strubbe [7] prepared buclizine by mixing hydrochloric acid
with 0.5 mol of 1-(p-tert-butylbenzyl)-piperazine 1, adding 0.5 mol
p-chlorobenzaldehyde2,andaddingdropwiseaqueous0.55Mpotassium
cyanide,thenheatingonawaterbathfor2h,yieldsanadditionproduct
whichisseparatedintolueneanddriedbeforereactionwithphenylmag-
nesiumbromide3togivebuclizine4.
O CH
3 MgBr
Cl CH + HN N CH2 CCHCH3 HCl, KCN, 3
3
2 1
Cl
CH
3
CH N N CH C CH
2 3
CH
3
4
Lui et al. [8] prepared buclizine by reducing p-chlorophenyl phenyl
ketone 1 with potassium borohydride to p-chlorobenzhydryl alcohol 2,
whichwasconvertedintop-chlorobenzhydrylbromide3.Thelattercom-
pound3waspreparedbyreactionofp-chlorophenylmagnesiumbromide
4 with benzaldehyde 5. p-tert-Butylbenzyl chloride 6 was condensed
directly with piperazine 7 to give p-tert-butylbenzylpiperazine 8. Treat-
mentofp-chlorobenzhydrylbromide3withp-tert-butylbenzylpiperazine
8 in the presence of anhydrous sodium carbonate gave buclizine 9
hydrochloride.
Buclizine 5
Cl Cl Cl
KBH H H O
C O 4 C C Cl MgBr + C
OH Br H
4 5
1 2 3
CH CH
3 3
ClH2C C CH3 + HN NH HN N CH2 C CH3
CH CH
3 3
6 7 8
Cl
H CH
CBr + HN N CH2 C C3H3 Na2CO3
CH
3
3 8
Cl
CH
3
CHN N CH C CH
2 3
CH
3
9
Cossementetal.[9]synthesizedtheenantiomersof1-(p-chlorobenzhy-
dryl)-4-(p-methylphenyl)sulfonylpiperazine3anduseditasaninterme-
diate for the preparation of buclizine 6 and other histamines. The
enantiomers of (þ)- and ((cid:4))-1-(p-chlorobenzhydryl)-4-(p-toluene sulfo-
nyl)piperazine3werepreparedandconvertedbyhydrolysistotheenan-
tiomersof(þ)-or((cid:4))-of p-chlorobenzhydrylpiperazine4.Compound 3
was prepared by refluxing p-chlorobenzhydrylamine 1 with N-bis-2-
chloroethyl-p-toluene sulfonamide 2 with ethyl diisopropylamine. Reac-
tionofp-tert-butylbenzylchloride5withp-chlorobenzhydrylpiperazine4
givesbuclizine6.
6 GamalA.E.MostafaandAbdullahA.Al-Badr
Cl
Cl CH CH O
2 2
CH NH2 + N S CH3 Ethyl diisopropylamine
Cl CH CH O
2 2
1 2
Cl Cl
O
CH N N S CH3 Hydrolysis CH N NH
O
3 4
Cl
CH
3
ClCH C CH
2 3
CH3 CH N N CH CCHC3H
2 3
5 CH
3
6
4. PHYSICAL CHARACTERISTICS
4.1. Solubility
Practically insoluble in water; sparingly soluble in chloroform and in
propane-1,2-diol;veryslightlysolubleinethanol(96%)[5].
4.2. Melting range
(cid:5)
230–240 C.
4.3. X-ray powder diffraction pattern
X-ray powder diffraction pattern (Fig. 1.1) has been obtained on D
8-Advanced Bruker AXE Germany, diffractometer equipped with
scintillation detector using copper Ka (¼1.5406 A˚) radiation with
scanning range between 2y and 50y at scanning speed of 2(cid:5) min(cid:4)1.
AfulldatasummaryiscompiledinTable1.1.
Buclizine 7
800
600
6.062 4.691
4200000 12.80012.100 7.3696.652 5.640 5.035 4.4144.1493.9663.7363.5733.4643.3863.3003.2293.0872.9962.9282.847 2.7042.650 2.5272.4472.3542.2912.2472.210 2.1062.047 1.971 1.8941.8751.826 1.748 1.685 1.6251.596
10,0000 20,0000 30,0000 40,0000 50,0000 60,0000
2q (°)
FIGURE1.1 X-raypowderdiffractionpatternofbuclizinehydrochloride.
4.4. Spectral properties
4.4.1. UV/VIS spectroscopy
The ultraviolet absorption spectrum of buclizine in methanol was
scanned from 200 to 400 nm, using UV/VIS spectrometer (Shimadzu
Ultraviolet-visible spectrophotometer 1601 PC) and is shown in Fig. 1.2.
The compound exhibited two maxima at 230 and 209 nm. Clarke [10]
reportedthefollowing:methanol255,260nm.
4.4.2. Infrared spectrum
The infrared absorption spectrum of buclizine (Fig. 1.3) was obtained in
KBr pellet using a Perkin-Elmer infrared spectrophotometer. The princi-
ple peaks were observed at 3051, 2961, 1093, 1604, 1312, and 1071 cm(cid:4)1.
Assignments for the major infrared absorption band are provided in
Table 1.2. Clarke [10] reported principal peaks at 1002, 1131, 754, 800,
1075,and694cm(cid:4)1.
4.4.3. Nuclear magnetic resonance spectrometry
1Hand13CNMRspectraofbuclizinewererecordedwithaVarianGemini
200spectrometer(200MHz).Chemicalshiftswereexpressedinpartsper
million with respect to the tetramethysilane (TMS) signal for 1H and
13CNMR.
4.4.3.1. 1H NMR spectrum The one-dimensional proton 1H NMR spec-
trum of buclizine base dissolved in CDCl is shown in Figs. 1.4 and 1.5.
3
The corresponding spectral assignments 1H NMR for buclizine are
providedinTable1.3.