FORMULATION AND EVALUATION OF NITROFURANTOIN

(MONOHYDRATE/MACROCRYSTALS) CAPSULES 100 MG

KOTA. DASHARATHRAM
Regd. No: 170617007
M. Pharm 2nd year- II semester
Industrial Pharmacy
Department of Pharmaceutics
Manipal College Of Pharmaceutical Sciences, MAHE

UNDER THE GUIDANCE OF

Dr. USHA Y NAYAK Mr. RAHUL MANORANJAN SAMMOHI

Associate Professor Scientist-IV, FRD,
Dept. of Pharmaceutics Aurobindo Pharma Limited
MCOPS, Manipal Research Center-I, Hyderabad.
 CONTENTS

1. TITLE OF THE STUDY

2. NEED FOR THE STUDY
3. RATIONALE/JUSTIFICATION FOR PROPOSED STUDY &
HYPOTHESIS
4. SIGNIFICANCE OF THE EXPECTED OUTCOMES
5. AIM &OBJECTIVES
6. STUDY DESIGN
7. MATERIALS &METHODS
8. REVIEW OF LITERATURE
9. PROGRESS IN STUDY
10. BIBLIOGRAPHY
 1. TITLE OF THE STUDY

FORMULATION AND EVALUATION OF NITROFURANTOIN

(MONOHYDRATE/MACROCRYSTALS) CAPSULES 100 MG
 2. NEED FOR THE STUDY
2A. Magnitude of problem:
• For any urinary tract infection, the site of action would be Uroepithelial cells
(Urothelium) located in lining of human urinary tract. So, maintaining the threshold
Antibacterial concentrations of any unchanged antibacterial drug in urine is vital in
order to get urinary tract infection treated, since urine is the only body fluid which will
be in contact with the urothelium.
• Nitrofurantoin is a BCS class IV drug with Maximum daily dose of 200 mg/day, Half-
life is about 60-80 minutes.
• Previously the Nitrofurantoin Immediate Release tablets USP 100 mg were
prescribed which are to be administered 4 times daily to reach the Minimum Effective
Concentration, this level of dose is above & beyond of what’s needed for achieving
therapeutic efficacy resulting in adverse effects.
2B. Work done so far:
• Nitrofurantoin Capsules USP 100 mg comprising Nitrofurantoin macrocrystals alone
with slower rate of dissolution & absorption in GIT, approved by USFDA in 1980’s
were marketed by Alvogen Malta operations Ltd.
• Nitrofurantoin Oral suspension USP 25mg/ml with increased bioavailability approved
by USFDA in 1980’s is made available by Casper Pharmaceuticals.
 NEED FOR THE STUDY cont’d

2C. The gaps in knowledge:

• Since the elimination half life of drug is as low as an hour, by the time drug reaches
Minimum Effective Concentration in urine, urine is excreted from the body. Optimum
dosage form has been marketed by the Warner Chilcott Ltd. so, this study is going to
conduct trials using different excipients with different compositions under same
dosage form as RLD.
2D. Unanswered questions regarding the research problem:
• Countless studies are conducted designing the formulation using other strategies, like
coating the Immediate release portion on the Sustained release or making a tab-in-
tab dosage form. Why they were all disapproved by USFDA ?
 3. RATIONALE/JUSTIFICATION FOR
3A. Proposed study:
The justification for proposed study is to carryout the trials of Nitrofurantoin capsules, by
taking the IR and SR portions combined in a capsule form, therefore by confirming the
dissolution profile matches with that of Reference listed drug, the formulation can be
marketed as a generic drug product.

3B. Research question:

What could be the composition of polymers to be used in the formulation to control the
drug release as of RLD ?

3C. Hypothesis:
We hypothesize that the formulation we are going to develop with certain composition is
going to meet the dissolution specifications of RLD.
4. SIGNIFICANCE OF EXPECTED OUTCOME
4A. Relevance to current scenario
• As of now, the dosage forms available are IR capsules & Suspension, which are
proven to be not so effective in treatment of urinary tract infection by their frequency of
administration and adverse effects caused by them.
• The present study is to formulate the capsules with both IR and SR portions which can
release the drug to appear in urine as soon as administered in to the body to achieve
the therapeutic level and show the action for prolonged period of time without any
decline in the antibacterial concentration of drug in urine of patient.

4B. Value Addition:

• The dissolution profile of this formulation is mapped with that of innovator to make it
available in the market as a generic product at a price that is affordable to every patient
suffering with acute and uncomplicated urinary tract infections.
• The adverse effects which are resulted from previous dosage forms are now resolved
due to the reduced frequency of administration, slow absorption & prolonged release of
this capsules and dose is with in the range of Maximum Daily Dose i.e. 200mg/day.
 5. AIM & OBJECTIVES
The aim of the present study is to design and formulate the Nitrofurantoin
(Monohydrate/Macrocrytals) capsules USP 100 mg to match the dissolution profile with
that of the Reference Listed Drug.
• Evaluation of Reference Listed Drug.
• Development of various formulations to prepare Nitrofurantoin
(Monohydrate/Macrocrytals) capsules using proper techniques.
• Study the effect of the concentration and type of Disintegrants on the formulation.
• Study the effect of the concentration of polymers on the formulation.
• To conduct the in vitro assay and establish the comparison chart with dissolution profile
of the RLD.
• Selection and optimization of the best formulation.
 6. STUDY DESIGN
The study design is framed as follows:
• Carryout a literature review on IR & SR characteristics in oral solids.
• Evaluation of Reference Listed Drug.
• Pre-formulation studies to know the Drug-Excipient compatibility
• Characterization of drug substances and other excipients for their physical and chemical
behaviour.
• Conduct “n” number of trials with different compositions of polymers.
• Test for physical parameters.
• In vitro assay and dissolution study.
• Comparison with marketed formulation or RLD.
• Selection of optimized formula based on the in vitro dissolution profile & other parameters
which are desirable to match with the Reference Listed Drug.
 7. MATERIALS & METHODS
MATERIALS:

Nitrofurantoin Macrocrystals
Nitrofurantoin Monohydrate
Lactose monohydrate USNF (Supertab 11SD)
Corn starch USNF (Uni-Pure FL)
Carbomer homopolymer (Type-B) USNF (Carbopol 974P NF polymer)
Povidone USP (Kollidone 90F)
Povidone USP (Kollidone 30)
Compressible sugar
Talc USP (Luzenac Pharma)
Magnesium stearate USNF (Ligamed MF-2-V)
Hard gelatin capsule shells (Opaque black/Opaque Yellow, Size-0, Z/66)
METHODS:

Digital balance
Electronic balance
UV-visible spectrophotometer
Rotary compression machine
Blender
Friabilator
Hardness tester
Disintegration apparatus
Dissolution apparatus
Glass ware
Sieve shaker
Coating machine
Tap density
 8. REVIEW OF LITERATURE
DRUG PROFILE

MACROCRYSTALLINE NITROFURANTOIN
DESCRIPTION
NITROFURANTOIN MONOHYDRATE
Molecular formula C8H6N4O5 C8H6N4O5. H2O
Molecular weight 238.16 256.17
1-[(5-nitrofurfurylidene)amino] 1-[(5-nitrofuran-2-yl) methylene
Chemical Name
hydantoin amino] imidazolidine-2,4-dione
Melting point 270-2720C 268.9 0C
Specific surface area Between 0.045-0.20 Not applicable
Slightly soluble in aqueous
solutions and alcohol & Soluble in organic solvents like
Solubility
soluble in organic solvents like DMF, DMSO
DMF, DMSO

Bulk Density (g/ml) 0.710 0.331

It doesn’t contain any

Isomerism It is non-chiral molecule
asymmetric carbon
 8. REVIEW OF LITERATURE cont’d
• Caira et al. reported two polymorphs of anhydrous Nitrofurantoin (α and β ) and two
polymorphs of Nitrofurantoin monohydrate (Form I and Form II). NF β polymorph and
monohydrate II are the stable anhydrate and monohydrate forms and exist in the
marketed formulations. The former has higher dissolution rate than the latter, which is
in accordance to the general observation that anhydrates tend to have higher
dissolution rates than hydrates.

• U.S. Pat. No. 3,458,622 issued to Hill on July 29, 1969, discloses controlled release
tablets which are produced by blending a medicament with polyvinylpyrrolidone and
carboxyvinylpolymer, granulating, drying, and compressing into tablets. The ratio of
polyvinylpyrrolidone:carboxyvinylpolymer in these controlled release tablets is from
about 1:10 to 10:1. Hill discloses that when the resulting tablet is placed in water or
gastric fluid, the two polymeric substances react to form a complex of low solubility
which is gumlike in consistency and retards the diffusion of the active material from
the tablet.
 8. REVIEW OF LITERATURE cont’d
• Pelletier Jr et al. concluded that Macrobid is more effective than macrodantin by conducting two
double-blind, active-controlled, randomized, outpatient, multicenter studies with identical
protocols to compare the efficacy and safety of Macrobid® (nitrofurantoin
monohydrate/macrocrystals), given 100 mg BID, with those of Macrodantin® (nitrofurantoin
macrocrystals), given 50 mg QID. Study drugs were administered for 7 days as therapy for acute
episodes of uncomplicated lower urinary tract infection (UTI). Nine hundred forty-four patients
(first study: Macrobid, n = 224; Macrodantin, n = 223; second study: Macrobid, n = 245;
Macrodantin, n = 252 were enrolled across 37 study sites in the United States. Assessable
patients (first study: Macrobid, n = 105; Macrodantin, n = 118; second study: Macrobid, n = 138;
Macrodantin, n = 136) were comparable in demographic and clinical characteristics. At 1 to 3
days post-treatment, rates of clinical success (i. e. clinical cure plus clinical improvement of
symptoms) ranged from 90% to 93% across treatment groups in the two studies; rates of
bacteriologic cure plus bacteriologic improvement from 88% to 92%; and rates of bacteriologic
cure, from 82% to 90. Thirty-one (3%) of the 944 enrolled patients withdrew from the studies
because of adverse events; of these patients, 19 reported nausea, either alone or in combination
with other events. This represents 2% (19/944) of the patients enrolled in the two studies. No
statistically significant differences in incidence rates or severity of any of the individual adverse
events were observed between the two treatment groups in either study. Results of these two
multicenter studies show that Macrobid 100 mg BID has the same bactericidal efficacy and the
same safety profile as those of Macrodantin 50 mg QID when given for 7 days for the treatment
of acute uncomplicated lower UTI. Given the added convenience of the BID dosing schedule for
Macrobid. It is oncluded that Macrobid is considered as an effective treatment.
 8. REVIEW OF LITERATURE cont’d

• U.S. Pat. No. 3,634,584 issued to Poole on Jan. 11, 1972, discloses a controlled
release tablet in which the controlled release is achieved by combining
carboxyvinylpolymer and polyethyleneglycol. Poole achieves a combination of rapid
release and sustained release by producing a two-layer tablet, one layer containing
the controlled release formulation and the other layer containing a formulation of the
active material which disintegrates rapidly to make the active material contained
therein quickly available.

• U.S. Pat. No. 4,772,473 describes pharmaceutical capsules for oral administration
containing a combination of sustained release/rapid release of nitrofurantoin, an
embodiment of which has been marketed under the trade name of Macrobid®. The
capsules of the '473 patent comprise separate portions of a first particulate mixture
and a second particulate mixture. The first particulate mixture comprises
nitrofurantoin, polyvinylpyrrolidone and carboxyvinylpolymer, while the second
particulate mixture comprises macrocrystalline nitrofurantoin.
 8. REVIEW OF LITERATURE cont’d

Carbomer:
• Carbomers are white-colored, ‘fluffy’, acidic, hygroscopic powders with a
characteristic slight odor.
• Carbomer is having low residuals of ethyl acetate, such as Carbopol 971P NF or
Carbopol 974P NF, may be used in oral preparations, in suspensions, capsules or
tablets. In tablet formulations, carbomers are used as controlled release agents
and/or as binders. In contrast to linear polymers, higher viscosity does not result in
slower drug release with carbomers. Lightly crosslinked carbomers (lower viscosity)
are generally more efficient in controlling drug release than highly crosslinked
carbomers (higher viscosity).
Functional Category
• Bioadhesive material; controlled-release agent; emulsifying agent; emulsion
stabilizer; rheology modifier; stabilizing agent; suspending agent; tablet binder.
 8. REVIEW OF LITERATURE cont’d

Hydroxypropyl Cellulose:
• Concentrations of 15–35% w/w of hydroxypropyl cellulose may be used to produce
tablets with an extended drug release. The release rate of a drug increases with
decreasing viscosity of hydroxypropyl cellulose. The addition of an anionic surfactant
similarly increases the viscosity of hydroxypropyl cellulose and hence decreases the
release rate of a drug. Blends of hydroxypropyl cellulose and other cellulosic polymers
have been used to improve wet granulation characteristics and tableting characteristics,
as well as to achieve better control and manipulation of the rate of drug release.

Functional Category
• Coating agent; emulsifying agent; stabilizing agent; suspending agent; tablet binder;
thickening agent; viscosity-increasing agent.
 9. PROGRESS IN STUDY

Evaluation of Reference Listed Drug:

Dissolution profile of RLD-NITROFURANTOIN CAPSULES 100 mg

Macrobid® (nitrofurantoin monohydrate/macrocrystals) Capsules 100mg; As per the PIL of

Macrobid capsules 100mg, it is claimed as “Meets USP Dissolution test 2”
USP Dissolution test 2:
Acid medium: 0.01 N hydrochloric acid for 1 h.
pH 7.5 buffer medium: run for an additional 6 h.
Volume of medium: 900 mL
Apparatus 2: 100 rpm, with sinkers made of Teflon-coated steel wire.
Time: 1, 3, and 7 h.
 The innovator details and dissolution data as follows:
RLD Product : Macrobid® (nitrofurantoin monohydrate/macrocrystals) Capsules 100 mg
Macrobid® (nitrofurantoin monohydrate/macrocrystals)
Capsules 100 mg
Unit No. (Reference Listed Drug Product)
Cumulative % of Nitrofurantoin Dissolved
1Hrs 2 Hrs 3 Hrs 5 Hrs 7 Hrs
Capsule 1 7.0 41.0 62.0 84.0 96.0
Capsule 2 6.0 41.0 63.0 84.0 96.0
Capsule 3 7.0 40.0 62.0 84.0 96.0
Capsule 4 7.0 40.0 62.0 84.0 96.0
Capsule 5 7.0 40.0 62.0 84.0 97.0
Capsule 6 7.0 40.0 63.0 84.0 96.0
Capsule 7 7.0 40.0 63.0 84.0 96.0
Capsule 8 7.0 40.0 63.0 85.0 96.0
Capsule 9 7.0 38.0 65.0 85.0 96.0
Capsule 10 7.0 40.0 64.0 84.0 96.0
Capsule 11 7.0 39.0 65.0 84.0 96.0
Capsule 12 6.0 41.0 64.0 84.0 96.0
Avg.(%) 6.8 40.0 63.2 84.2 96.1
Min(%) 6.0 38.0 62.0 84.0 96.0
Max(%) 7.0 41.0 65.0 85.0 97.0
SD 0.4 0.9 1.1 0.4 0.3
 10. BIBLIOGRAPHY

• Sustained release dosage form of Nitrofurantoin- U.S Patent: US4122157A issued to Warner
Chilcott ltd., in the year 1991.
• M. R. Caira, E. W. Pienaar and A. P. Lötter, Mol. Cryst. Liq. Cryst., 1996, 279, 241.
• https://www.accessdata.fda.gov/scripts/cder/ob/search_product.cfm - Orange Book: Approved
Drug Products with Therapeutic Equivalence Evaluations.
• https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=BasicSearch.process -
Drugs@FDA: FDA Approved Drug Products.
• Mintzer, S., E. R. Kadison, W. H. Shlaes & O. Felsenfeld, "Treatment of Urinary Tract
Infections with a New Antibacterial Nitrofuran", Antibiotics & Chemotherapy, Vol. 3, No. 2
(February 1953), pp. 151-157.
• Pelletier Jr, L.L. & Michalak, D.P. & Carter, J.Z. & Daughtry, J.D. & Madden, R.A. & Barnard, L
& Berkman, N.L. & Arciola, A.J. & Hackman, R.H. & Hughes III, T.M. & Smith, J.W. & Ellis,
K.E. & Rudolph, L.A. & McClung, T.S. & Fischer, L.A.. (1992). A comparison of Macrobid®
(nitrofurantoin monohydrate/macrocrystals) and Macrodantin® (nitrofurantoin macrocrystals) in
the treatment of acute episodes of uncomplicated lower urinary tract infections. Advances in
Therapy. 9. pp: 32-45.
• Handbook of Pharmaceutical Excipients, 6th edition, Edited by Raymond C Rowe, Paul J
Sheskey, Marian E Quinn, published in 2009, pp: 110-114 & 317-321.