Prepared by :ziyad salman

Supervised by :dr.Abdnaser zaid

Preformulation study of moxifloxacine

Hcl
Preformulation study of moxifloxacin hydrochloride

1. Introduction
Moxifloxacin is a synthetic fluoroquinolone antibiotic agent. These
are quinolines in which the quinoline ring system is substituted by
a carboxyl group at one or more positions. It has activity against
Gram-positive pathogens and maintenance of activity against
Gram-negative organisms. [1]

1.1Chemical Name: 1-Cyclopropyl-6-fluoro-1,4-dihydro-8-

methoxy-7-((4as,7as)-octahydro-6H-pyrrolo(3,4-b)pyridin-6-yl)-4-
oxo-3-quinolinecarboxylic acid. [1]

1.2Chemical Formula: C21H25ClFN3O4[1]

1.3Chemical Structure:

[1]
1.4 Molecular weight: 401.4314 [1]
1.5 Melting point: 324-325°C(dec.) [1]
1.6 Protein binding: 50% bound to serum proteins, independent
of drug concentration.[1]
1.7 Half-life: 11.5-15.6 hours (single dose, oral) [1]
1.8 Appearance: Almost white to yellowish crystalline
powder[1]
1.9 Solubility: In water, 1146 mg/L at 25 °C (est)[2]
1.10 Derivatives: moxifloxacin is a quinolone/fluoroquinolone
antibiotic related to ciprlevofloxacin, enoxacin, fleroxacin,
gatifloxacin, gemifloxacin, grepafloxacin, lomefloxacin,
levofloxacin, norfloxacin, levofloxacin, pefloxacin, prulifloxacin,
rufloxacin, sparfloxacin, temafloxacin, trovafloxacin,
sitafloxacin.[3]
1.11 Hygroscopicity: moxifloxacin HCl is hygroscopic

1.12 Specification:
Characteristics Almost white to yellowish
crystalline powder
Identification Positive [4]
Solubility Positive [4]
Ionization constants Amphoteric . Two pKa values
were 6.25 and 9.29 [4]
Optical activity Moxifloxacin HCl has two
chiral centers leading to
possible formation of four
different isomers[4]
Polymorphism Moxifloxacin HCl exists in
different forms[4]
1.13 Overdose: In the event of overdose, symptomatic treatment
should be implemented. ECG monitoring should be
undertaken, because of the possibility of QT interval
prolongation administration of charcoal with a dose of 400 mg
oral moxifloxacin will reduce systemic availability of the drug by
more than 80%.[5]
1.14 Pharmacology: Moxifloxacin is a new 8-methoxyquinolone.
moxifloxacin achieves extensive penetration into lung tissues
and suggest that the antibiotic should be active against
 pathogens located in mucosae and in the interstitium, e.g. S.
pneumoniae and H.influenzae, as well as against intracellular
organisms like Chlamydia and Legionella. Does not require dose
adjustment for renal or, most probably, hepatic impairment.
There are no significant effects of age or gender on
moxifloxacin pharmacokinetics and pharmacodynamics. [6]
1.15 Pharmacokinetics: absorbtion Pharmacokinetics of
moxifloxacin after single doses were linear within the range 50
to 800mg. Rapid absorption of moxifloxacin was observed,
within 1 to 4 hours after treatment, and absolute bioavailability
was high(82to89%). The plasma half-life (t1⁄2) ranged from 11.4
to 15.6 hours, depending on dose, and indicates that a once-
daily dosage regimen (e.g. 400mg)is suitable. Distribution :it
has been shown that moxifloxacin rapidly penetrates into
maxillary sinus mucosa following five oral doses of 400mg,
reaching peak levels of 7.47 mg/kg after 3 hours post-
administration The corresponding plasma concentration of
moxifloxacin was 3.80 mg/L. Similar findings were obtained for
anterior ethmoid mucosa and nasal polyps Metabolisim:
Metabolites of moxifloxacin identified in humans are the N-
sulfate (M-1) and the acyl-glucuronide (M-2). Phase II
metabolism was only observed in humans. M-1 was highly
bound to plasma protein (about90%),whereas only10%ofM-
2wasproteinbound. Neither of these metabolites has any
antimicrobial activity. Execretion Moxifloxacin is eliminated via
metabolic, renal and biliary/faecal pathways. Approximately
22% of unchanged compound, 18% of the glucuronide and
3.5% of the sulpho-compound are excreted via the kidneys.
Unchanged moxifloxacin was excreted in both urine and faeces,
M-1 was excreted mainly via the biliary/faecal route, whereas
 M-2 was excreted via the kidneys and was not detected
infaeces. [6, 7]
1.16 Mechanism of action: a broad-spectrum antibiotic . active
against both Gram-positive and Gram-negative bacteria. It
functions by inhibiting DNA gyrase, a type II topoisomerase,
and topoisomerase iv,8 which is an enzyme necessary to
separate replicated DNA, thereby inhibiting cell division. [7]
1.17 Interactions: The bioavailability of moxifloxacin (400mg)
was reduced when it was co administered with anantacid or
sucralfate (1g). Absorption of moxifloxacin 400mg was
significantly decreased by co-administration of an iron
preparation. . moxifloxacin did not show any clinically
interaction with theophylline(400mg twice daily) ,probenecid
(500mg twice daily) ,warfarin (25mg) or oral contraceptives. [7]

1.18 Indications: a-Community-Acquired Pneumonia

Moxifloxacin (administered 400mg once daily) the eradication
rates for moxifloxacin were 90 to 100% for S. pneumoniae, 85
to 100% forH. influenzae, 100% for M. catarrhalis and K.
pneumoniae, 89 to 92% for
C.pneumoniaeand93to96%forM.pneumoniae.b- Acute
Exacerbations of Chronic Bronchitis , moxifloxacin 400mg
administered once daily for 5 or 10 days. Eradication rates
against other common pathogens (M. catarrhalis, S.
pneumoniae, S. aureus, K. pneumoniae and H. para
influenzae) . No strains resistant to moxifloxacin. C- Acute
Sinusitis , Seven- and 10-day courses of moxifloxacin once daily
. [7, 8]
Other indication : Bacterial Conjunctivitis, Ocular bacterial infections,
Skin-structure infections, Post-operative infection.
1.19 Significant drug interactions: moxifloxacin and other
medicinal products that may prolong the QTc interval cannot
be excluded. This might lead to an increased risk of ventricular
arrhythmias. Therefore, co-administration of moxifloxacin
with :1- anti-arrhythmics class IA (e.g. quinidine,
hydroquinidine,). 2- anti-arrhythmics class III (e.g.
amiodarone).3- antipsychotics (e.g.
phenothiazines,haloperidol) 4- tricyclic antidepressive agents.5-
certain antihistaminics (terfenadine)[6, 8]
1.20 Paediatrics: (<18 years of age)moxifloxacin is not
recommended for children under the age of 18 years [8]
1.21 Pregnancy & Lactation: safety not established[8]
1.22 Elderly: safe [8]
1.23 Purity: Not less than 99%
1.24 Side-Effects: nausea, diarrhea, Dizziness, slightly higher
incidence of gastrointestinal event, lower incidence of CNS
events. Cardiac Effects: ,the use of moxifloxacin should be
avoided in patients with congenital or acquired syndromes of
QTc prolongation or in those receiving concomitant drugs
known to prolong the QTc interval.[7]
1.25 Contraindication: the use of moxifloxacine is
contraindicated for who are hypersensitive to MOXIFLOXACIN
(moxifloxacin hydrochloride) or other quinolone antibacterial
agents, or who are hypersensitive to any ingredient in the
formulation or component of the container. [8]

1.26 Adverse effects: slightly higher incidence of gastrointestinal

event, lower incidence of CNS events, low phototoxic potential
 due to the methoxy group , chondro toxicity and tendon
disorders, Transient elevations in liver enzyme levels were
observed after administration of moxifloxacin 45 or 135 mg/kg
for 3 to 6 months. [6]
1.27 Storage: Store it at room temperature and away from
excess heat and moisture, should be kept in tightly closed
containers protect from light .[2]

2. Preformulation Study
2.1 Method: Identification of Drug:
UV/VIS spectroscopy : e UV/VIS absorption spectrum of
moxifloxacin HCl monohydrate (0.0043 mg/ml as anhydrous) in
methanol. The two maxima, recorded at 232 and 295 nm, are
apparently due to the p!p* electronic transitions in the aromatic
ring.[4]
HPLC analysis of drug: Carry out the test as described under
1.14.1 Thin-layer chromatography using silica gel R5 as the coating
substance and a mixture of 4 volumes of 1-butanol R, 4 volumes of
methanol R and 2 volumes of ammonia (~100 g/L) TS as the mobile
phase. Apply
separately to the plate 10 µL of each of the following 2 solutions: for
solution (A), use a
0.05 mg/mL solution of the test substance in methanol R. For
solution (B), use a 0.05 105
mg/mL solution of moxifloxacin hydrochloride RS in methanol R.
Develop the plate for
a distance of 15 cm. After removing the plate from the
chromatographic chamber allow
it to dry in air or in a current of air. Examine the chromatogram
under ultraviolet light
(365 nm). The principal spot in the chromatogram obtained with
solution (A) corresponds in
position, appearance and intensity with the spot due to moxifloxacin
in the chromatogram
obtained with solution (B)[2]
Mass spectrometry: The mass spectra of moxifloxacin HCl
monohydrate was carried out using the quadrupole ion trap mass
spectrometry (QITM) and Fourier transform ion cyclotron resonance
mass spectrometry (FTICRMS) analyzer , both equipped with an
electrospray ionization (ESI) source.
It was suggested that the fragment ions at m/z 181 and 169 are
formed by cleavage of a benzene ring, while the fragment ion at m/z
145 is probably formed by the migration of a fluorine atom to
nitrogen followed by cleavage of the NdC bond, fragment ion at m/z
364 is formed by loss of HF leading to the formation of the four-
membered ring azetidine. [4]
2.2 Preformulation Study Of Drug: Preformulation studies are
needed to ensure the development of a stable as well as
therapeutically effective and safe dosage form. The Preformulation
studies, performed in this research include identification of drug,
solubility analysis, partition coefficient and drug compatibility.[3]
2.3 Solubility determination : According to the WHO, EMA, and
USFDA guidelines , moxifloxacin HCl can be considered as a highly
soluble drug based on the Biopharmaceutics Classification System
(BCS). The drug exhibits a dose/solubility (D/S) of <250 ml over the
pH range.[4]

2.4 Melting point determination: The melting point was

measured using the Bu ¨chi B-450 device by the capillary
technique, the melting point of moxifloxacin HCl monohydrate
increases with the heating rate. [4]
2.5 Partition coefficient determination:- The apparent partition
coefficients of moxifloxacin (log Papp) in 1-octanol/ buffer
systems were measured at different pH values (5.9–8.7), The
 true partition coefficient (log P) value was calculated using the
apparent partition coefficients and the micro-ionization
constants and was found to have a value of 0.832, Based upon
the high drug solubility and high permeability, moxifloxacin HCl
can be classified as BCS Class I drug. [4]

Po/w = (Coil/C aq .) equilibrium

3. Results And Discussion

3.1 Organoleptic Properties
3.1.1 Colour: a slightly yellow to yellow
3.1.2 Crystalinity: crystalline powder
3.1.3 Hygroscopicity: slightly hygroscopic
3.1.4 Taste: Bitter
3.1.5 Odour: odorless
3.1.6 Identification of Drug: The longest wavelength between 320
and 380 nm

4. Discussion:
4.1 FT-IR Study for identification of drug:
FT-IR spectroscopy The FT-IR absorption spectrum of moxifloxacin
HCl from Sigma was recorded using the JASCO FTIR 460 PLUS (KBr
disc) in the range of 4000–400 cm. FT-IR technique can be used to
distinguish between different forms of anhydrous and hydrate
moxifloxacin HCl. For example : moxifloxacin HCl monohydrate
(Form II) has characteristic IR bands in the region of 36003100
cm1 (OH valency vibrations) corresponding to water of
crystallization.
4.2 Solubility properties:
Solubility of moxifloxacin in different solvents is recorded .

the solubility of moxifloxacin HCl is pH dependent ,it increases

with pH (above 6) due to the ionization of the carboxylate group
(pKa1¼6.4). The reduction in the solubility below pH 2 is due to
the common-ion effect by chloride ions.

60

50

40
Solubility
(mg/ml)

30

20

10

0
0 1 2 3 4 5 6 7 8
pHeq

4.3 Partition Coefficient:

apparent partition coefficients of moxifloxacin (log Papp) in 1-
octanol/ buffer systems, and was found to have a value of
0.832[4]
4.4 Melting Point : 324-325°C(dec.)

4.5 IR interpretation of drug:

Wavenumber (cm1) Assignmen
3150- 3050 V(o_H,N_H)
3120 V(=(C_H)
3000-2800 V(C_H)
1711 V(C=O)
1619 V(C=C)
1433 V(CH2)
1376–1352 V (Quinolone ring)

Calibration Curve: The UV/VIS absorption spectrum of

moxifloxacin HCl (0.0043 mg/ml as anhydrous) in methanol.

S. No. Drug Conc. Absorbance

1 397.036 mg/tab t 293Nnm
2 399.984 mg/tab 382 nm
3 398.352 mg/tab 302 nm
REFRENCES
1. https://www.drugbank.ca/drugs/DB00218. Available from:
https://www.drugbank.ca/drugs/DB00218.
2. https://pubchem.ncbi.nlm.nih.gov/source/hsdb/8026 HSDB is a toxicology
database that focuses on the toxicology of potentially hazardous chemicals.
It provides information on human exposure, industrial hygiene, emergency
handling procedures, environmental fate, regulatory requirements,
nanomaterials, and related areas. The information in HSDB has been
assessed by a Scientific Review Panel.]. Available from:
https://pubchem.ncbi.nlm.nih.gov/source/hsdb/8026.
3. Shahwal, V.K., B. Dubey, and M. Bhoumick, Preformulation study of
levofloxacin. Int. J. Adv. Pharm., 2012. 1.
4. Al Omari, M.M.H., et al., Moxifloxacin Hydrochloride. 2014. 39: p. 299-431.
5. Chen, X., et al., QT prolongation and proarrhythmia by moxifloxacin:
concordance of preclinical models in relation to clinical outcome. British
Journal of Pharmacology, 2005. 146(6): p. 792-799.
6. Wise, R., A Review of the Clinical Pharmacology of Moxifloxacin, a New 8-
Methoxyquinolone, and its Potential Relation to Therapeutic Efficacy.
Clinical Drug Investigation, 1999. 17(5): p. 365-387.
7. Barman Balfour, J.A. and H.M. Lamb, Moxifloxacin. Drugs, 2000. 59(1): p.
115-139.
8. Tulkens, P.M., P. Arvis, and F. Kruesmann, Moxifloxacin Safety. Drugs in
R&D, 2012. 12(2): p. 71-100.
Table 1: Composition of Brand moxifloxacine hcl

Component Function
Moxifloxacine Active
Microcrystalline cellulose FILLER
Croscarmellose sodium DISINTEGRANT
Magnesium stearate LUBRICANT
Lactose monohydrate FILLER
Hypromellose Film coat
Macrogol 4000
Ferric oxide (E172)
Titanium dioxide (E171

Table 2: Physicochemical characterization of Brand moxifloxacine hydrochloride tablet

400 mg .

DESCRIPTION Dull red film-coated tablet with an oblong, convex

shape with facet, a dimension of 17 x 7 mm, and
marked with “M400” on one side and “BAYER” on
the other side.
BATCH # Up104
EXPIREY DATE Oct 24
STRENGTH(MG) 400
SCORE NO
COATING film-coated tablets

Disintegration Time 15-45 min

Assay (%w/w of label claim) 100% w/w of label claim
any other individual impurity Unspecified impurities:NMT 0.1%
Tabel 2: Quality Target Product Profile (QTPP) for Generic moxifloxacin HCL tablet
400mg

QTPP Elements Target Justification

Dosage form TABLET Pharmaceutical equivalence
requirement: same dosage
form
Dosage design FILM-COATED IMMEDIATE Immediate release design
RELEASE TABLET needed to meet label claims
Route of administration ORAL Pharmaceutical equivalence
requirement: same route of
administration

Dosage strength 400mg Pharmaceutical equivalence

Pharmacokinetics Immediate release enabling
Cmax of 2.5 mg/h was
reached in 1.5 h (tmax) and
AUC was 26.9 mg/h
Stability At least 6 month shelf life at
room temp
Drug product quality Physical Attributes
attributes Identification
Assay
Content Uniformity
Dissolution
Degradation Products
Residual Solvents
Water Content
Microbial Limits
36 months in aluminium foil
Container closure system strips or blister packs.
24 months in HDPE bottles
(not marketed in the UK)
Administration/Concurrence Similar food effect as RLD
with labeling
requirement: same strength
Bioequivalence requirement
Needed to ensure rapid
onset and efficacy
Equivalent to or better than
RLD shelf-life
Pharmaceutical equivalence
requirement: Must meet the
same compendial or other
applicable (quality)
standards (i.e., identity,
assay, purity, and quality).
Needed to achieved the
target shelf life and to
ensure tablet integrity during
shipping
can be taken with or without
food .

Alternative methods of None None are listed in the RLD

 administration label

Table 3 : Critical Quality Attributes (CQAs) of Generic moxifloxacin HCL TABLET

400mg .
QUALITY ATTRIBUTES OF TARGET IS THS JUSTIFICATIONS
DRUG PRODUCT CQAs?
Physical Appearance Color and shape NO Color, shape and
Attributes acceptable to the appearance are not
patient. No visual tablet directly linked to
defects observed. safety and efficacy.
Therefore, they are
not critical. The
target is set to ensure
patient acceptability
Odor No unpleasant odor NO neither the drug
substance nor the
excipients have an
unpleasant odor. No
organic solvents will
be used in the drug
product
manufacturing
process.
Size Similar to RLD NO For comparable ease
of swallowing as well
as patient acceptance
and compliance with
treatment regimens,
the target for tablet
dimensions is set
similar to the RLD
Score UNSCORED AND FILM- NO EASE FOR
configuratio COATED DISINTEGRATION AND
n ACCEPTABLE TASTE
Friability NMT 1.0% w/w Yes Friability is a routine
test per compendial
requirements for
tablets. A target of
NMT 1.0% w/w of
mean weight loss
assures a low impact
on patient safety and
efficacy and
minimizes customer
complaints.
Identification POSITIVE FOR YES Though identification is
moxifloxacin HCL critical for safety and
efficacy
Assay 100% w/w of label claim YES Assay variability will
affect safety and
efficacy.
Content Uniformity (CU) Conforms to USP YES Variability in content
 <905>Uniformity of uniformity will affect
Dosage Units safety and efficacy
Dissolution Limits 95.0–105.0% (as No Failure to meet the
moxifloxacin) dissolution
Medium 0.1 N HCl; 900 specification can
ml Time: 45 min impact
Dissolution apparatus 2 bioavailability.
50 rpm
Unspecified Yes Degradation products
Degradation Products impurities:NMT 0.1% can impact safety and
Total:NMT0.5% must be controlled
based on
compendial/ICH
requirements or RLD
characterization to
limit patient exposure
Water Content The maximum water YES Drug is slightly
uptake (<0.1%) hygroscopic
Microbial Limits Meets relevant YES Non-compliance with
pharmacopoeia criteria: microbial limits will
The total aerobic impact patient safety
microbial
count:NMT1000cfu/g The
total combined mold
sand yeasts
count:NMT100cfu/g[<61>
and<62>]
Rsidual solvent Proceed as directed the YES NO solvent is used in
general chapter[<467>] the drug product
manufacturing process
and the drug product
complies with USP
Option 1. Therefore,
formulation and
process variables are
unlikely to impact this
CQA.