CHRONO THERAPEUTIC DRUG DELIVERY SYSTEM OF SALBUTAMOL SULPHATE FOR THE TREATMENT OF ASTHMA

CHRONO THERAPEUTIC DRUG DELIVERY SYSTEM OF
SALBUTAMOL SULPHATE FOR THE TREATMENT OF ASTHMA
Guided by Presented by
Mrs M.SuryaPrabha., M.Pharm., M.G.Prasanna lakshmi,B.Pharm,
Assistant professor Y12MPH413
Department of Pharmaceutics Including Industrial Pharmacy
CHALAPATHI
chalapathi institute of pharmaceutical
INSTITUTE OF PHARMACEUTICAL SCIENCES, GUNTUR - 522034
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CONTENTS
• Research project – Introduction
• Research question and Hypothesis
• Research project - Objectives
• Research Problem statement
• Literature Review
• Research Methodology
• Calendar of ResearchWork
• Status of the ResearchWork
• Research findings
• Results and Discussion
• Summary and Conclusion
• References
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RESEARCH PROBLEM : INTRODUCTION
Therapeutic Area Selected
Sustained and controlled drug delivery system release the drug at a substantially steady rate of release per
unit of time. However, there are instances where maintaining a constant blood level of a drug is not desirable.
In such cases a pulsatile drug delivery may be more advantageous. Pulsatile drug delivery systems (PDDS)
are gaining importance as these systems deliver the drug at specific time as per the path physiological need of
the disease resulting in improved patient therapeutic efficacy and compliance. Diseases where in PDDS are
promising In asthma treatment
Exisisting Formulations
Aerocart200(inhaler),Asthacure(syrup),Aerocort(Rotocap)
Necessity For Improved Drug Delivery /Dosage Forms
in case of inhaler,syrup,rotocap
there is immediate action of drug with in less time later the action subsides to over come this
problem,extended release pattern drug release can be achieve by tablet in capsule device method
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RESEARCH QUESTION(S) AND HYPOTHESIS
Example: Research questions
• How does the process variables will effect the productivity of dosage form with quality, efficacy and
safety? Or how are the process variables effected the drug release and principle parameters of the dosage
form(specify parameters).
•What is effect of direct compression on the percentage of drug release characteristics of salbutamol
sulphate.
•Which of the substances in the study will be effective to serve as effective releasing of drug(salbutamol
sulphate).
•What are the effect of erodible compressed polymers concentration on the physical and drug release
characteristics
• how does the salbutamol sulphate made to release as pulse from insoluble capsule body to manage
asthmatic attacks during midnights or early morning hours.
Examples of Hypothesis:
• The affect of direct compression can extend the release of drug at early morning hours or midnights .
• The direct compression technique will give highest percentage of entrapment efficiency
• The effect direct compressd drug can prolong the drug release
• The ability of erodible compressed polymers as better release retardant for the pulse release of salbutamol
sulphate
• The generic product (tablets/capsule) are in-vitro bioequivalent with innovator product.
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RESEARCH PROJECT: OBJECTIVES
Preformulation Studies
Fundamental Formulation :
 Solubility
Permeability
Polymorphism
PH Stability
Derivative Formulation :
Micromeritic Behavior
In vitro Dissolution Studies for an ER Tablet
In vitro Dissolution Studies for an IR Powder
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RESEARCH PROBLEM: STATEMENT and RATIONALE
• Research Problem Statement
To increase the time of action of drug & To save the patients from asthmatic effects during
sleep time & to improve patient compliance
• Rationale of Research work
♦ Slowly erodible polymers & control plug over drug
♦ Asthmatic effects are generally seen during night times due to cold climate
♦ Lower daily cost to patient due to fewer dosage unit are required
♦ Reduced dosage frequency
♦ Improved patient compliance
♦ Reduction in dose size
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SALBUTAMOL SULPHATE
• Section:Respiratory System Sub Section:Asthma, COPD
• Drug Class:Beta2 agonists, short-acting
SIDE EFFECTS:
• Shakiness In The Legs, Arms, Hands, Or Feet
• Trembling Or Shaking Of The Hands Or Feet
Dose :
• Dose: 2-4 mg oral, 0.25-0.5 mg i.m. /s.c., 100-200 ].lg by inhalation
Time of action
• Inhaled salbutamol produces bronchus dilatation within 5 min and the
action lasts for 2-4 hours. It is, therefore, used to abort and terminate
attacks of asthma, but is not suitable for round the-clock prophylaxis
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MONOGRAPH :
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MONOGRAPH of EXCEPIENTS:
MATERIAL GRADE/BRAND USE
HYPERMELLOSE K 100M,K15M RATE-CONTROLLING
POLYMER
LACTOSE ANHYDROUS EXCELLENT
COMPRESSIBILITY
PROPERTIES
MICRO CRYSATLLINE
CELLULOSE
GRADE 12 EMULSIFIER
MAGENSIUM STEARATE VEGETABLE FRADE-NON
BOVINE
ANTI ADHERENT
AEROSIL 200 ANTI CAKING AGENT
SODIUM CARBOXY
METHOXY CELLUOSE
AQUALON THICKNER
SODIUM STARCH
GLYCOLATE
GLYCOLYS ABSORBS WATER RAPIDLY,
RESULTING IN SWELLING
WHICH LEADS TO RAPID
DISINTEGRATION
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MONOGRAPH OF DRUG SUBSTANCE:
S.No Physicochemical
Characteristics
Drug substance an Salbutamol sulphate
IUPAC Nomenaclature Bis[(1RS)-2-[(1,1-dimethylethyl)amino]-1-[4-hydroxy-3-
(hydroxymethyl)phenyl]ethanol] sulphate
Molecular formula C26 H44 N2 O10 S
Molecular Weight 576.7
Specification of Drug
substance
Protected from light.
Dissociation Constant pKa 10.12
Solubility
(Solvents and specific
value from literature)
2.15g/l , Soluble in water and methanol , slightly soluble
in ethanol.
Pharmacokinetic parameters
Intestinal Absorption 0.9812
Volume of distribution 156 +/- 381
Elimination rate constant
and half-life
Approximately 72% of dose is excreted in the urine
within 24 hours, 28% as unchanged drug and 44% as
metabolite..1 to 2 hours
Therapeutic window 108μg-7.5mg
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LITERATURE REVIEW:
S.No Authors Title of the
publication
Drug
substance
Product Ref. No
Past work on drug substance
1 Graham The use of
isothermal
microcalorimetry in
the study of
changes in
crystallinity of spray-dried
salbutamol
sulphate
Albuterol
sulphate
International
Journal of
Pharmaceutics
Pg num
113-
118
2 carbal Studies of cyclodextrin
inclusion complexes. I.
The salbutamol-cyclodextrin
complex as
studied by phase
solubility and DSC
salbutamol International
Journal of
Pharmaceutics
Pg num
259-
266
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Preformualtion and formulation
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1 ANDERSON Broncho dialating action of
salbutamol sulpahte
comparision of inhalers to
powder
SALBUTAMOL EUROPEAN
RESPIRATORY
JOURNAL
PG NUM
10-14
2 CHAWLA Production of spray dried
salbutamol sulphate for use in dry
powder aerosol formulation
Albuterol sulphate International
Journal of
Pharmaceutics
Pg num
233-240
Analytical Studies
1 Dr. Sohan.
Chitlange
RP-HPLC method for estimation of
salbutamol sulphate & theophylline albuterol
sulphate &
theophylline
OMICS
JOURNAL
PAGE NUM
45-48
Invivo studies
1 Babu
vb,khar rk
In vitro and in vivo studies of
sustained-release floating dosage
forms containing salbutamol
sulfate
Albuterol
sulphate
European
pubmed
Pg num 268-
270
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RESEARCH METHODOLOGY:
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Materials used
MATERIAL GRADE/BRA
ND
HYPERMELLOSE K 100M,K15
LACTOSE ANHYDROUS
MICRO CRYSATLLINE
GRADE 12
CELLULOSE
MAGENSIUM
STEARATE
VEGETABLE
FRADE-NON
BOVINE
AEROSIL 200
SODIUM CARBOXY
METHOXY CELLUOSE
AQUALON
SODIUM STARCH
GLYCOLATE
GLYCOLYS
Equipment
1)Dissolution apparatus (USPI and
USP II)
2)Tablet punching machine(7mm)
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• Formulation of IR Powder (Immediate Release Powder)
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INGREDIENTS FORMULATION
F1
mg/tab
F2
mg/tab
F3
mg/tab
F4
mg/tab
F5
mg/tab
SALBUTAMOL 2 2 2 2 2
MCC 50 97.57 97.57 146 72.57
LACTOSE MONOHYDRATE 98 50.43 50.43 - 73.43
SSG 3 3 5 5 5
AEROSIL 1 1 1 1 1
MAGNESIUM STEREATE 1 1 1 1 1
TOTAL WEIGHT 155 155 157 155 155
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• Formulation of ER Tablets(Extend Release Tablets)
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INGREDIENTS FORMULATION
F1
mg/tab
F2
mg/tab
F3
mg/tab
F4
mg/tab
F5
mg/tab
F6
mg/tab
F7
mg/tab
SALBUTAMOL 6 6 6 6 6 6 6
HPMC K100M - - 50 75 50 60 37.5
HPMC K15 50 75 - - - - -
SODIUM CMC 25 - 25 - - 37.5
MCC 18 18 18 18 43 33 18
MAGNESIUM STEREATE 1 1 1 1 1 1 1
TOTAL WEIGHT 100 100 100 100 100 100 100
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PREPARATION METHOD: TABLET IN CAPSULE METHOD
• Prepare Immediate Release powder & next Extend Release tablet
• For ER tablet maintain punch 5-7Kg/cm2
• In capsule first fill ER Tablet & next with coating of erodible polymer &
later filled with IR powder.
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RESEARCH FINDINGS:
• Calibration of drug substance and analytical methodology:
1. UV Spectrum:
UV scanning was done for pure drug 200-400 nm in methanol. The λ max was found at 276nm
Preparation of Standard Calibration Curve for Salbutamol sulphate:
Reagents
Methanol
0.1N Hydrochloric acid Buffer Solution
Principle:
Standard solution of Salbutamol sulphate by using 0.1 N HCL:
100mg of drug is dissolved in 100ml of methanol. This is first stock solution.10ml of 1st
stock solution is diluted with 100ml of 0.1N Hydrochloric acid buffer. This is 2nd stock
solution. Now from 2nd stock, various concentrations of 2ug/ml, 4ug/ml, 6ug/ml, 8ug/ml, and
10ug/ml were prepared by using same 0.1 N Hydrochloric acid buffer. Blank was also
prepared with same buffer composition except the drug. All the samples were analyzed at 276
λ max with respect to the blank.
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STANDARD PLOT OF SALBUTAMOL SULPHATE FOR 0.1N HCL
concentration
(μg/ml) absorbance
0 0
2 0.097
4 0.18
6 0.27
8 0.35
10 0.45
λ max - 276
STANDARD PLOT OF SALBUTAMOL
0.5
0.45
0.4
0.35
0.3
0.25
0.2
0.15
0.1
0.05
SULPHATE FOR 0.1 N HCL
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y = 0.044x + 0.003
R² = 0.9999
0
0 2 4 6 8 10 12
ABSORBANCE
CONCENTRATION(μg/ml)

RESEARCH FINDINGS:
• Calibration of drug substance and analytical methodology:
1. UV Spectrum:
UV scanning was done for pure drug 200-400 nm in methanol. The λ max was found at 276nm
Preparation of Standard Calibration Curve for Salbutamol sulphate:
Reagents
Methanol
PH 6.8 Phosphate buffer
Preparation of 6.8 pH phosphate buffer solution:
27.22g of monobasic potassium phosphate was weighed and diluted up to 1000 ml to get
stock solution of monobasic potassium phosphate. 8g Sodium hydroxide was weighed and
diluted up to 1000ml to get 0.2M sodium hydroxide solution. 50 ml of the monobasic
potassium phosphate solution was taken from the stock solution in a 200-mL volumetric
flask and 22.4 ml of sodium hydroxide solution from stock solution of 0.2M sodium
hydroxide solution was added and then water was used to make up the volume.
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• Standard solution of Salbutamol sulphate by using pH 6.8
Buffer Solution:
100mg of drug is dissolved in 100ml of methanol. This is first stock
solution.10ml of 1st stock solution is diluted with 100ml of 6.8 buffer. This is
2nd stock solution. Now from 2nd stock, various concentrations of 10ug/ml,
20ug/ml, 30ug/ml, 40ug/ml, and 50ug/ml were prepared by using same 6.8
buffers. Blank was also prepared with same buffer composition except the
drug. All the samples were analyzed at 276 λ max with respect to the blank
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RESEARCH FINDINGS:
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STANDARD PLOT OF SALBUTAMOL SULPHATE FOR 6.8
PHOSPHATE BUFFER
λ max - 276
STANDARD PLOT OF SALBUTAMOL
SULPHATE FOR PH 6.8 PHOSPHATE
Conc. BUFFER
(μg / ml)
0.35
0.3
0.25
0.2
0.15
0.1
0.05
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y = 0.006x + 0.002
R² = 0.9999
0
0 10 20 30 40 50 60
ABSORBANCE
concentration(μg/ml)
Absorbance at λMax = 276 nm
0 0
10 0.061
20 0.126
30 0.186
40 0.239
50 0.302

MICRO MERITIC STUDY : IR POWDER
Formulation
Code
Bulk density
(Kg/cm3)
Tapped
density
(Kg/cm3)
Cars index Hausners
ratio
Angle of
repose ()
F1 0.610 0.714 14 1.17 17.9
F2 0.590 0.685 13 1.16 22.8
F3 0.640 0.667 15 1.15 20.02
F4 0.621 0.756 17 1.12 24.09
F5 0.652 0.653 15 1.14 24.08
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MICRO MERITIC STUDY : ER TABLET
Formulation
Code
Bulk density
(Kg/cm3)
Tapped
density
(Kg/cm3)
Cars index Hausners
ratio
Angle of
repose ()
F1 0.40 0.48 16 1.2 12.73
F2 0.39 0.48 18 1.23 11.96
F3 0.50 0.58 13 1.16 11.58
F4 0.44 0.50 12 1.1 9.92
F5 0.37 0.41 9.75 1.1 11.14
F6 0.37 0.41 9.75 1.1 11.03
F7 0.36 0.39 7.6 1.0 11.85
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In vitro Dissolution Studies for Salbutamol sulphate ER Tablets
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Time
(Hrs)
%Drug Released In 6.8 PH BUFFER, USP II, 50 Rpm
F1 F2 F3 F4 F5 F6 F7
0 0 0 0 0 0 0 0
1 8 8 5 4 6 6 8
2 15 17 10 10 15 15 17
4 40 35 21 18 29 24 30
6 60 50 34 28 43 40 42
8 82 64 50 41 54 51 55
12 93 77 61 53 65 61 70
16 94 88 75 66 81 75 84
20 - 96 94 80 96 91 95
24 - 98 96 84 97 93 96
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• In vitro Dissolution Studies for an Salbutamol sulphate IR Powder
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Time
(Mins)
% drug released in 0.1 N HCL, USP I, 50 rpm
F1 F2 F3 F4 F5
0 0 0 0 0 0
10 35 50 60 50 52
15 65 75 75 76 76
30 82 82 90 90 91
45 86 87 96 94 95
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Extennded Release Tablets
• The Carr’s index and Hausner’s ratio were found to be in the range of ≤ 18 and 1.0
to 1.23 respectively, indicating good flow and compressibility of the blends.
• The angle of repose for all the formulations was found to be in the range of 9.92-
12.73˚ which indicating Excellent flow.
Immediate Release Powder
• The Carr’s index and Hausner’s ratio were found to be in the range of ≤ 18 and 1.12
to 1.17 respectively, indicating good flow and compressibility of the blends.
• The angle of repose for all the formulations was found to be in the range of 17.9-
24.09˚ which indicating Excellent flow.
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RESULTS and DISCUSSION

• The standard calibration curve of Salbutamol sulphate in 6.8 phosphate buffer
showed Good correlation with regression value of 0.9999. 6.8 phosphate buffer for
ER Tablets invitro dissolution studies.
• The standard calibration curve of Salbutamol sulphate in 0.1 N HCL buffer showed
Good correlation with regression value of 0.9999. 0.1N HCL buffer for IR Powder.
invitro dissolution studies
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INVITRO DISSOLUTION STUDIES OF SALBUTAMOL SULPHATE
ER TABLET and IR POWDER

INVITRO DISSOLUTION STUDIES FOR SALBUTAMOL SULPHATE
Comparative dissolution
profile for f3, f4 and f5 (IR
120
100
80
60
40
20
Zero order plot for best
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Comparative dissolution
profile for f1 and f2 (IR
100
80
60
40
20
0
powder)
0 10 20 30 40 50
CUMULATIVE % DRUG RELEASE
TIME(MIN)
F1
F2
0
powder)
0 20 40 60
TIME(MIN)
F3
F4
F5
120
100
80
60
40
20
0
formulation (f3)
0 20 40 60
TIME (MIN)
F3
Higuchi plot for best
150
100
50
0
formulation(f3)
0 5 10
%DRUG
RELEASE
SQUARE ROOT OF TIME
Series1
Series2
Linear (Series1)
Linear (Series1)
IR POWDER

• Among the different Diluents and binders 97.57 mg/tab and
50.43 mg/tab showing highest drug release retarding capacity.
• F3 was showing the satisfactory results.
• Higuchi plots F3 formulation is having good correlation values
so the drug is releasing diffusion mechanism
• When we plot the release rate kinetics for best formulation F3
was following zero order.
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COMPARATIVE DISSOLUTION
PROFILE FOR F1, F2 AND F3
COMPARATIVE DISSOLUTION
PROFILE FOR F4, F5, F6 AND F7
150
100
50
FIRST ORDER PLOT FOR BEST
150
100
50
HIGUCHI PLOT FOR BEST
FORMULATION (F2)
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INVITRO DISSOLUTION STUDIES FOR SALBUTAMOL SULPHATE
ER TABLETS
120
100
80
60
40
20
0
(ER TABLETS)
0 10 20 30
TIME(HRS)
F1
F2
F3
0
(ER TABLETS)
0 5 10 15 20 25 30
TIME (HRS)
F4
F5
F6
F7
2.5
2
1.5
1
0.5
0
FORMULATION (F2)
0 10 20 30
LOG % DRUG RETAINED
TIME(HRS)
Series1
Series2
Linear (Series1)
0
Linear (Series2) -50
0 2 4 6
% DRUG RELEASE
SQUARE ROOT OF TIME
F2

• Among the different control release polymers HPMC k15m
was showing highest drug release retarding capacity
• F2was showing the satisfactory results and having better
sustainability
• When we plot the release rate kinetics for best formulation F2
was following first order because correlation coefficient value
of first order is more than zero order to value.
• F2 formulation diffusion exponent n value is 0.45 < n >0.89
so they are following Anomalous( Non- Fickian) diffusion
• Higuchi plots F2 formulation is having good correlation values
so the drug is releasing diffusion mechanism
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From the experimental data, it can be concluded that
• HPMC K15M was respectively showed better Pulsatile drug release of Salbutamol sulphate
• When drug : polymer concentration increases the release rate decreases this is because of
reason when the concentration of polymer increases the diffusion path length increases
• Formulated tablets showed satisfactory results for various Post compression evaluation
parameters like: tablet thickness, hardness, weight variation, floating lag time, total floating
time, content uniformity and in vitro drug release.
• F2 Formulation gave better-controlled drug release and in comparison to the other
formulations of ER Tablets.
• The release pattern of the F2 formulation of ER Tablet was best fitted to Korsmeyer-Peppas
model, Higuchi and first-order model.
• The most probable mechanism for the drug release pattern from the formulation was
Anomalous( Non- Fickian) diffusion
• F3 formulation gave better results and in comparison to the other formulations of IR Powder.
• The release pattern of the F3 formulation of IR Powder was best fitted to Higuchi and zero –
order model.
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SUMMARY and CONCLUSION

Calendar of Research Project:
Please shade the cells blue for finished work and Red for unfinished work.
DEC JAN FEB MAR APR MAY JUN JUL AUG SEP OCT NOV
SRP
PRW
LS
PRM-1
BW
PRM-2
TM
JP
PRM-3
TS
SRP: submission of research proposal; PRW: Project Review work plan; LS: Literature survey; PRM:
project review Meeting; TM: Thesis Making; JP: Journal Publication; TS: Thesis Submission to
Review chair.
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Status of the Research Project:
Timeline-
Status
DEC JAN FEB MAR APR MAY JUN JUL AUG SEP OCT NOV
SRP
PRW & LS
PF
OFP
EP
SS
In-VIVO
SRP: submission of research proposal; PRW: Project Review work plan; LS: Literature survey; PF:
Preforrmulation; OFP: optimization of formulation; EP: Evaluation of Parameters SS: Stability studies;
INVIVO.
Please shade the cells – Red : not completed; Green: completed; yellow : to initiate
process; Blue in process.
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1. Shivakumar HG, Pramod kumar TM, Kashppa GD. Pulsatile drug delivery
system, Indian J Pham Educ 2003;37(3):125
2. Ramesh D. Parmar, Rajesh K. Parikh, G. Vidyasagar, Dhaval V. Patel,
Chirag J. Patel, Biraju D. Patel. Pulsatile Drug Delivery Systems: An
Overview. Int J Pharma Sci and Nanotechnology. 2009; 2(3):605-614
3. Botti B, Youan C: Chronopharmaceutics: gimmick or clinically relevant
approach to drug delivery, Jorn. Control. Rel. 2004; 98(3): 337-353
4. http://thred.org/wp-content/uploads/2010/06/circadian-body-e128300967472...
assessed on 1-2-2011
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Acknowlegements:
The students are thankful to the chalapathi educational society for
providing facilities to carry out this research work.
We express our gratitude to Sri. Y.V.Anjaneyulu, president chalapathi
educational society, guntur.
We are indebted to Dr. Rama Rao Nadendla Ph.D., F.I.C, Principal, CIPS
for providing all facilities throughout the course and arranged all equipments
for the students to carry out the research work and exposure .
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CHRONO THERAPEUTIC DRUG DELIVERY SYSTEM OF SALBUTAMOL SULPHATE FOR THE TREATMENT OF ASTHMA

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