1. Formulation and evaluation of modified release
(MUPS) tablet of class I drug for controlling of
hypertension
Presented by
Miss. S. A. Kulkarni
M.Pharm (Pharmaceutics) IV sem
Guided by
Ms. S. P. Dhamane
M. Pharm (Pharmaceutics)
JSPM’S
Jayawantrao Sawant College of Pharmacy and Research, Hadapsar
Pune-28
Formulation and evaluation of modified release
multiple unit pellets (MUPS) tablets of class I drug for
controlling hypertension
4/3/2021
2. • Introduction
• Review of literature
• Need and objectives of work
• Justifications
• Plan of work
• Profile of drug
• Materials and methods
• Results and discussion
• Summary and conclusion
• References
CONTENTS
CONTENTS
4/3/2021
4. • Hypertension
• High blood pressure is the leading risk factor for death claiming 1.5 million lives each
year.
• One in three adults in the Region has high blood pressure.
• Males have a slightly higher prevalence of high blood pressure than females in almost
all countries of the Region.
• Hypertension (HTN) or high blood pressure, sometimes called arterial hypertension, is
a chronic medical condition in which the blood pressure in the arteries is elevated.
• Blood pressure is summarized by two measurements, systolic and diastolic which
depend on whether the heart muscle is contracting (systole) or relaxed between beats
(diastole).
INTRODUCTION
4/3/2021 1
5. • High blood pressure is said to be present if it is often at or above 140/90 mmHg. If
the blood pressure rises too high, it can cause harmful effects
Types of Hypertension:
Table No 1 Classification of hypertension
Causes of hypertension
• Overweight Smoking
• High cholesterol level Family history with HBP
• Diabetic
Classification
Systolic BP
(mmHg)
Diastolic BP
(mmHg)
Normal <120 and <80
Pre-hypertension 120-139 or 80-89
Stage 1 Hypertension 140-159 or 90-99
Stage 2 Hypertension >160 and >100
4/3/2021 2
6. Treatment of hypertension
4/3/2021 3
Sr
No
Class Drugs Dosage form
1 (ACE) inhibitors Captopril, Enalapril Tablet ,capsule
2 (ARBs) blockers Telmisartan, Losartan Tablet
3 Diuretics Chlorothiazide Tablet
4 Beta blockers Atenolol, Metoprolol Tablet
5 Calcium channel
blockers
Verapamil, Amlodipine Tablet, capsule
Table No 2 Treatment of hypertension
Sr No Beta Blockers Trade Name Usual Dosage Range
1 Propranolol Inderal, generic
Inderal
20-120 mg BID
60-240 mg daily
2 Nadolol Corgard, generic 20-160 mg daily
3 Timolol Blocadren, generic 5-20 mg BID
4 Atenolol Tenormin, generic 25-100 mg daily
5 Metoprolol Betaloc, Lopressor, generic
Lopressor SR
25-100 mg BID
100-200 mg daily
7. Multiple unit pellets system (MUPS)
• The tablets which are prepared by compaction of modified
release coated pellets are called as MUPS tablets.
• Pellets are produced for the purpose of oral controlled release
dosage form having gastro resistant or sustained release
properties.
• For such purpose, coated pellets are administered in the form of
MUPS tablets. The coating material used is either sustained
release or enteric release.
• Different release profile can be achieved at same time at same
site in GIT.
4/3/2021 4
8. Advantages
• Minimize drug accumulation with chronic dosing.
• Limited risk of local irritation.
• No risk of dose dumping.
• Flexibility of dose design.
• Reduce dosing frequency of drugs.
• Maintain therapeutic concentrations.
• Patient compliance.
• Increase the safety and stability of
dosage form.
4/3/2021 5
10. Literature Review of drug candidate
Table No 3 Literature for disease
Sr No Title Other Method Polymers
1 Formulated modified
release tablet of MTS
Gohel M.C Wet granulation
method
xanthan gum
,HPMC
2 Developed a new,
precise and simple UV
spectrophotometric
methods
Jadhav A UV and
derivative
spectroscopy
phosphate
buffer 6.8
(solvent was
used)
4/3/2021 6
Sr No Title Author About
1 Reviewed on systemic
hypertension
Wilbert S A They studied about
elevated BP, with its
diseases.
2 Reviewed on hypertension
(HTN) d blood pressure
Nandhini.S chronic medical
condition ,life style
Table No 4 Literature of drug candidate
11. Literature for dosage form
Table No 5 Literature for dosage form
4/3/2021 7
Sr No Title Author Method Polymer
1 Designed and optimised
extended release MTS
tablet
Vanita J melt
granulation
technique
HPMC,
stearic
acid,MCC
2 Formulated and
evaluated modified-
release multiple-unit
tablets of loratadine and
pseudoephedrine
hydrochloride
Farrukh Z extrusion–
spheronization
method
Ethyl cellulose
,MCC
3 Formulated modified
release tablet of MTS
using multiple unit
pellets system
Gharge V Wruster
process
HPMC K4M,
HPMC K15M,
HPMC
K100M.
Carbopol
13. Disorder Global status
controlled release due to pellets
Drug antihypertensive drug (β blocker)
Dosage form Multiple unit pellet tablet
NEED OF WORK
• β blockers are the choice of antihypertensive at second stage of hypertension
• The selected drug is class I drug (high solubility and high permeability) it
required to controlled its release.
• The half life of drug was 3-4 hrs.
• Conventional dosage form dose dumping may cause.
• Required modified release dosage form.
• MUPS system overcome above problems.
NEED AND OBJECTIVE
4/3/2021 8
14. OBJECTIVE OF THE STUDY:
The present study is planned with the following objectives:
1.Preformulation studies:
Characterization of drug and excipients.
Drug-Excipient compatibility studies.
2.Formulation and evaluation of modified release multiple unit tablet of BCS
class I drug for treatment of hypertension.
3.Stability studies of the most satisfactory formulation as
per ICH guidelines at storage condition(25±2°C,60±5%) (40±2°C, 75±5%)
4/3/2021 9
16. JUSTIFICATIONS
Justification of selection of drug
• Drug is official in IP, BP, USP. Hence the standard of purity,
identity and quality are established.
• It is effective agenized hypertension and myocardial infraction.
• After a single oral dose, peak plasma concentration occurs
after about 1 to 2 h.
• The drug is eliminated within 3 to 4 h which.
• Conventional dosage forms are not effective as much .
• It meets essential criteria for CDDS.
4/3/2021 10
17. Selection of dosage form
• Maintain therapeutic concentrations
• Controlled release of drug and may offer an improved
bioavailability.
• Overcomes dose dumping and minimizes side effects
associated with it.
• Pellets as a drug delivery system offer not only technological
advantages but also better flow properties, less friable dosage
form, narrow particle size distribution, ease of coating.
JUSTIFICATIONS
4/3/2021 11
19. PLAN OF WORK
Selection of suitable
formulation
additives
Selection of
suitable drug
candidates
Procurement of drugs, formulation additives and
packaging material
Characterization of
drug candidate
Characterization of
formulation additives viz.
polymers etc.
Selection of
suitable drug
delivery system
Selection of suitable
label, primary
packaging system
Review of literature
Characterization of
primary package
4/3/2021 12
20. a. Description
b. Organoleptic properties- Color, odor
and taste
c. Solubility in different solvents
d. Spectral characteristics- UV
spectroscopy, IR spectroscopy
e. Thermal characteristics - Melting
range
a. Description
b. Organoleptic properties – Color, odor
taste
c. Solubility in different solvents.
d. Spectral characteristics – IR spectroscopy
e. Thermal characteristics - Melting range
Formulation and Evaluation of MUPS
Formulation and Evaluation of MUPS
tablet
4/3/2021 13
21. stability studies on the most satisfactory
formulation as per ICH guidelines at storage
condition(25±2°C,60±5%) (40±2°C, 75±5%)
Compilation and analysis of data and
interpretation of results
4/3/2021 14
23. β1 selective blocker
• Official status : Official monograph in IP,BP,USP NF.
• Synonym: β1 selective blocker
Fig 1:Chemical structure of MTS
• Chemical name:
• (RS)-1-(Isopropyl amino)-3-[4-(2-methoxyethyl)phenoxy]propan-2-ol
• Empirical formula: C34H56N2O210
• Molecular weight:652.81584 g/mol
• Category: Antihypertensive
4/3/2021 15
24. • Pharmacokinetics:
Absorption: absorption of MTS is rapid and complete.
Distribution : distributed high plasma protein binding (99.5%)
mainly albumin and α1 -acid glycoprotein.
Metabolism: MTS is metabolized predominantly by CYP2D6
enzyme.
Elimination: Eliminated unchanged in feces via biliary excretion.
• Pharmacodynamic: It block the beta cells present in to the
heart leading to decrease cardiac output.
4/3/2021 16
25. • Mechanism of action
• MTS competes with adrenergic neurotransmitters such as
catecholamines for binding at β1-adrenergic receptors in the
heart. β1-receptor blocked results in a decrease in heart rate,
cardiac output, and blood pressure.
4/3/2021 17
Fig 1 mechanism of drug
27. Characterization of MTS
• Organoleptic properties
Such as colour, odor ,taste, appearance and physical state.
• Physicochemical characteristics viz. Solubility in different
solvents.
• Spectrophotometric characterization using
UV- Visible spectrophotometry
IR spectrometry.
Determination of thermal behavior.
Melting range.
EXPERIMENTAL
4/3/2021 18
28. Characterization of formulation excipients.
• Formulation of tablet was developed using various additives
viz, microcrystalline cellulose pellets, HPMC K4M, Eudragit
NE30D, PVPK30, Perlitol, talc, Ethyl cellulose 15cps,and they
were characterized for following
• Physicochemical properties.
• Thermal behavior.
• Melting range.
• Spectrophotometric characterization using FTIR spectrometry
Interaction between drug and additives:
• Visual inspection
• FTIR study
4/3/2021 19
29. Formulation development of (MUPS) tablet of antihypertensive drugs:
• Table No 6: Formulation of drug loaded (MUPS)
• Note- Each ingredients were weighed in mg
Formulation FS1 FS2 FF3 FF4 FF5 FF6 FCR7 FCR8
API 50 50 50 50 50 50 50 50
MCC pellets 100 100 100 100 100 100 100 100
PVP K30 3.6 3.6 3.6 3.6 3.6 3.6 3.6 3.6
HPMCK4M 8.5 8.5 8.5 8 8 8 8.5 10
DMW QS QS QS QS QS QS QS QS
Drug loaded
pellets
162.1 162.1 162.1 161.6 161.6 161.6 162.1 163.6
4/3/2021 20
Parameter Set Values Parameter Set Values
Inlet Temperature 600C ± 500C Peristaltic Pump RPM 1 to 2
Bed Temperature 420C Perforated plate Type C
Outlet air Temperature 420C Partition diameter / length 74 / 250 mm
Inlet air Pressure 1 to 2 bar Distance partition-plate 1cm
Spraying nozzle Diameter 1.2 mm Filter Air purging Pressure 1-3bar
Liquid Spray 1-3 bar
30. • Procedure for preparation of drug loaded pellets
PVP K 30 was weighed accurately
and transfer it in to water to prepare
solution .In that solution HPMC K4M
was added slowly
Measured quantity of MCC pellets was
added in to the FBP chamber and FBP
was started .
Prepared PVP and Drug solution was
sprayed on to the MCC pellets and
dried.
Prepared drug loaded pellets were
evaluated for Pellet size ,Flow
properties, LOD, Drug contents
4/3/2021 21
31. a)Seal coating (FS1 to FS2)
• Table No 7: Formulation of seal coating MUPS
Ingredients FS1 FS2
HPMC E5 3(2%) 4.87(3%)
Talc 1.2 1.2
Isopropyl alcohol 9.5 9.5
Methylene dichloride 0.5 0.5
DMW QS QS
Seal coated pellets 176.3 178.1
4/3/2021 22
Parameter Set Values Parameter Set Values
Inlet Temperature 600C ± 500C Peristaltic Pump RPM 1 to 2bar
Bed Temperature 420C Perforated plate Type C
Outlet air Temperature 420C Partition diameter / length 74 / 250 mm
Inlet air Pressure 1 to 2 bar Distance partition-plate 1cm
Spraying nozzle Diameter 1.2 mm Filter Air purging Pressure 1-3bar
Liquid Spray nozzle
Pressure
1-3 bar
FBP conditions
32. • Preparation of seal coated pellets
From above drug loaded pellets FS1 and
FS2 formulation was seal coated
Weighed accurately HPMC E5,and
transfer in the solution of IPA:MDS
with distilled water
The above solution was sprayed on the
drug loaded pellets in FBP at suitable
pumping rate , and dried after some
time
Prepared seal coated pellets were
evaluated for Pellet size, Flow
property,LOD,Drug contents
4/3/2021 23
33. b) Functional coating (FF3 to FF6)
• Table No 8: Preparation of MUPS for functional coating
FBP conditions
Ingredients FF3 FF4 FF5 FF6
Eudragit NE 30D 3.16(3%) 3.11(2%)
HPMC 15 cps - - 3.12(2%) 4.72(3%)
Talc 3 3 3 3
Isopropyl alcohol 9.5(ml) 9.5(ml) 9.5(ml) 9.5(ml)
Methylene dichloride 0.5(ml) 0.5(ml) 0.5(ml) 0.5(ml)
DMW QS QS QS QS
Total weight 178.26 177.61 177.72 179.32
4/3/2021 24
Parameter Set Values Parameter Set Values
Inlet Temperature 600C ± 500C Peristaltic Pump RPM 0.5to 2bar
Bed Temperature 400C Perforated plate Type C
Outlet air Temperature 400C Partition diameter / length 74 / 250 mm
Inlet air Pressure 1 to 2 bar Distance partition-plate 1cm
Spraying nozzle Diameter 1.2 mm Filter Air purging Pressure 1-3bar
Liquid Spray nozzle Pressure 1-3 bar
34. • Preparation of functional coated pellets
From drug loaded pellets the FF3 to FF6
formulations were functional coated
In formulation FF3 and FF4 for coating
Eudragit NE 30 D was used and
prepared with help of IPA:MDC in
distilled water ,sprayed on the drug
loaded pellets in FBP
For the formulation FF5 and FF6 the
polymer was change as HPMC 15 cps all
the procedure same as above
Prepared pellets were evaluated for Pellet
size, LOD, Drug content.
4/3/2021 25
35. C) Control release coating (FCR7, FCR8)
• Table No 9: preparation of control release coating MUPS
FBP conditions
Ingredients FCR7 FCR8
Ethyl cellulose 15 cps 3.19(2%) 4.1(3%)
Talc 1.2 1.2
Isopropyl alcohol 9.5 9.5
Methylene dichloride 0.5 0.5
DMW QS QS
total weight 176.49 178.9
4/3/2021 26
Parameter Set Values Parameter Set Values
Inlet Temperature 600C ± 500C Peristaltic Pump RPM 0.5to 2bar
Bed Temperature 400C Perforated plate Type C
Outlet air Temperature 400C Partition diameter / length 74 / 250 mm
Inlet air Pressure 1 to 2 bar Distance partition-plate 1cm
Spraying nozzle Diameter 1.2 mm Filter Air purging Pressure 1-3bar
Liquid Spray nozzle Pressure 1-3 bar
36. • Controlled release coated pellets
For the FCR7 and FCR8 formulation
controlled release coating was applied
In this coating Ethyl cellulose 15 cps solution
was sprayed on to the drug loaded pellets , in
the FBP at particular pump speed
Prepared controlled release pellets were
evaluated for Pellets size, LOD, SEM, Drug
contents.
4/3/2021 27
37. Preparation of tablets
• Table No 10: Table preparation of MUPS tablet
Evaluation of tablets
• Thickness and Dimension
• Weight variation
• Hardness
• Friability
• Drug content
• In-vitro drug release
• Stability study
Ingredients FS1 FS2 FF3 FF4 FF5 FF6 FSR7 FSR8
Previous weight of
pellets
176.3 178.1 178.26 177.61 177.72 179.32 176.49 178.9
Perlitol 40 40 40 40 40 40 40 40
Placebo MCC pellets 140.1 138.3 138.14 138.79 138.68 137.08 139.91 137.5
Mg stearate 3.6 3.6 3.6 3.6 3.6 3.6 3.6 3.6
Total weight 360 360 360 360 360 360 360 360
4/3/2021 28
38. • Preparation of tablets
From each formulation pellets were collected
weighed accurately and in that perlitol and
MCC pellets were added
The above blend was mixed properly in to
double cone blander for 20 min and then add
Mg stearate in that
The above blend were compressed by direct
compression machine, which having 11mm
punch , tablet were formulated and evaluated
4/3/2021 29
40. • Characteristics of MTS drug
• Table No.11: Physicochemical characteristics of MTS
RESULTS AND DISCUSSION
Characteristics Reported
Experimental
Finding
Description
Physical state Solid Solid
Appearance Amorphous powder Amorphous powder
Organoleptic properties
Color Off white Off white
Odour Odorless No particular odor
Taste Moderately bitter Moderately bitter
Melting range 1050C– 1070C 1050C-1070C
Physicochemical properties
Water Freely soluble Freely soluble (clear solution)
Ethanol (95%v/v) Soluble Soluble (clear solution)
4/3/2021 30
41. • IR characteristics of MTS
:(RS)-1-(Isopropylamino)-3-[4-(2-methoxyethyl)phenoxy]propan-2-ol
Fig 4: IR spectrum of sample MTS
Table No 7: Interpretation of infra red spectrum of MTS
Peak
No
Observed
Frequency (cm-
1)
Probable functional group and
type of molecular vibration
1 3565 cm-1 N-H Stretching
2 3123 cm-1 O-H Stretching
3 2991 cm-1 C-H Stretching
4 2827 cm-1 C-H Stretching of CH2
5 1552 cm-1 Aromatic ring Stretching
6 1378cm-1 N-H Stretching of secondary amine
4/3/2021 32
42. • Drug excipients interaction study
Fig 5 Infrared spectrum of physical mixture of MTS: MCC , MTS:PVP K30, MTS: Ethyl cellulose ,MTS:HPMC K4M
4/3/2021 33
43. Evaluation of drug loaded pellets
• Flow and compressibility of Pellets
Compressibility index and angle of repose in the range of 11-14% and 24-26⁰
respectively which indicates good flow property
• Pellets size
All pellets mostly passed through sieve No 40.up to 60% of pellets were passed from
that sieve.250 μm
• Loss on drying
The % moisture content was below 1% which is acceptable
• Determination of drug loading.
Drug loading on all pellets were found to be 90 to 96%.
4/3/2021 34
44. Seal coating (FS1 to FS2)
• Flow and compressibility of Pellets
Table No 11 :Physical evaluation of seal coated pellets
Pellets size was in range 250 μ
Determination of drug loading content Scanning Electron Microscopy
Pellets size
4/3/2021 35
Sr.
No Formulation
code
Angle of
Repose(0)
Compressibi
lity Index%
Tapped
density
(gm/cm3)
Bulk
density
(gm/cm3)
1 FS1 23.28 12.56 0.53 0.42
2 FS2 24.15 12.86 0.51 0.40
Formulation % drug loading
FS1 82.10%
FS2 80.12%
Table No6: Scanning Electron microscopy
45. • Functional coating (FF3 to FF6)
• Flow and compressibility of Pellets
• Table No 12 :Flow and compressibility of functional coating Pellets
Pellets size
Pellets size was in range 350 μ
Determination of drug loading content
The % drug loading was found to be 90-92%
Scanning Electron Microscopy
4/3/2021 36
Sr. No
Formulati
on code
Angle of
Repose(0)
Compressibi
lity
Index %
Tapped
density(g
m/cm3)
Bulk
density(gm/
cm3)
1 FF3 25.45 12.56 0.56 0.48
2 FF4 23.15 12.48 0.62 0.52
3 FF5 25.45 13.54 0.64 0.51
4 FF6 25.68 14.56 0.65 0.52
Table No7: Scanning Electron microscopy
46. • Control release coating (FCR7, FCR8)
• Flow and compressibility of Pellets
• Table No 13 : Flow and compressibility of control
Pellets size
Determination of drug loading content
Table No 14:Determination of drug loading release Pellets
Sr. No Formulation Encapsulation
efficiency in %
1 FCR7 96.50%
2 FCR8 97.22%
Scanning Electron microscopy
Table No8: Scanning Electron microscopy
4/3/2021 37
Pellets
Formulati
on code
Angle of
Repose(0)
Compressibility
Index
%
Tapped density
(gm/cm3)
Bulk density
(gm/cm3)
Drug
loaded
pellets
FCR7 23.12 12.89 0.52 0.40
FCR8 22.15 11.23 0.56 0.42
47. • Evaluation of tablet
Table No 15:Physical evaluations of tablets
Sr. No Formulation
code
Thickness
mm
Hardness
Kg/cm3
Friability
%
Drug
content%
1 FS1 3.85±0.08 4.25±0.21 0.59±0.02 99.62
2 FS2 3.89±0.02 4.15±0.5 0.55±0.05 95.97
3 FF3 3.88±0.01 4.25±0.12 0.78±0.02 96.77
4 FF4 3.76±0.04 4.45±0.45 0.72±0.03 98.92
5 FF5 3.79±0.03 4.23±0.21 0.48±0.01 99.92
6 FF6 3.88±0.02 4.84±0.54 0.35±0.03 99.96
7 FCR7 3.79±0.05 5.0±0.15 0.40±0.04 97.55
8 FCR8 3.84±0.05 4.24±0.23 0.37±0.01 99.84
4/3/2021 38
Thickness: was found in range of 3.5-4mm
Hardness: was in range of 4-5Kg/cm2.
Friability: As per USP friability of tablet NMT 0.8%
Drug content: was found to be 97.55to99.62 % which was acceptable as per USP.
48. • Stability study of selected formulation
Table No 16 : Stability of (MUPS) tablets
• From above study it was concluded that, no significant change in the physical properties and
drug content of tablet. Therefore formulation was stable
4/3/2021 40
Test Specification Initial 1 month
25ºc±2º/60% 40ºc±2º/75%
appearance Circular tablet Complies Complies Complies
dissolution 2(NMT 25%) 12.31 10.84 12.30
4(20-40) 31.25 29.23 30.45
8(40-60) 55.23 54.63 55.12
20(NLT 80%) 98.25 97.25 97.12
50. • The drug and other excipients possess requisite specifications which
confirm their identity, purity and quality.
• The FTIR spectral studies indicated that, there was no interaction between
polymer and drug.
• Polyvinylpyrrolidone and talc were added to the coating solution to
increase layer stability and to prevent pellet agglomeration.
• The findings of the present study demonstrate that the developed controlled
release platform with HPMC and EC could slow down the release profile
of MTS from their matrices.
4/3/2021 41
51. • Release kinetics analysis showed that drug release from formulations was
adequately described by zero-order equation.
• This approach for development of platform will be suitable for
controlled delivery of highly soluble drugs such as MTS and other
Class I drug.
• Formulation is stable at exaggerated condition of temperature and
humidity (40 ± 20C & 75±5%)
• Developed (MUPS) tablets are very reliable to extend release of
MTS over period of 24 hrs (in vitro).and covers the major period of
the day where symptoms of Hypertension could be fatal.
4/3/2021 42
53. 1. Marvin M et al .Major cardiovascular disorders. Yale university
school medicine heart book:149-50
2. http://www.cardiresearch.org/topic/hypertension /hypertension-
India
3. http://en.wikipedia.org/wiki /hypertension
4. Gharge V et al .multiple-unit controlled release platform
formulation by wruster process, International Journal of Pharmacy
and Pharmaceutical Sciences:Int J Pharm PharmSci, Vol 6; Issue 2:
107-113
5. Nandhini.S et al.Essential Hypertension –A Review Article,J.
Pharm. Sci. & Res. Vol. 6(9), 2014, 305-307
4/3/2021 43
54. 6. Shailesh L P et al.controlled release approach to novel
multiparticulate drug delivery system.ijps. Vol 4, issue 3, 757-763
7.Farrukh Z et al ,formulation and evaluation modified-release multiple-
unit tablets of loratadine and pseudoephedrine
hydrochloride2014;vol4;2(3):1470-72
8. http://en.wikipedia.org/wiki/MTS
9.http://www.drugs.com/international/MTS.html
10.http://www.ncbi.nlm.nih.gov/pubmed
11.The United State Pharmacopoeia. Asian edition.2010; 4435,4442
4/3/2021 44
55. 12.Jadhav A. S, Tarkase K. N et al Quantitative Determination of MTS in bulk and tablet
Dosage form through comparative study of UV and derivative Spectroscopy; Der
Pharmacia Lettre, 2012, 4 (3):763-767
13.Farrukh Z et al ,formulation and evaluation modified-release multiple-unit tablets of
loratadine and pseudoephedrine hydrochloride2014;vol4;2(3):1470-72
14.Rowe R,Paul S,Owen C.Handbook of pharmaceutical excipients.5th
ed.UK:Pharmaceutical press;2011:449-51
15.Martindale: The complete drug reference, 34th edition, Edited by- Sean C. Sweetman,
Pharmaceutical Press Publication, 728
4/3/2021 45