M Pharm final presentation i.e. IV Sem.

1. Formulation, development & evaluation of modified release
centrally acting capsules of skeletal muscle relaxants.
Presented By
Mr. Bhosale Pramod
Motiram
M. Pharm. (SEM- IV)
Pharmaceutics
Roll No-02
Seat No.:- 10123
Guided By-
Prof. A. W. Ambekar
M. Pharm. Pharmaceutics
Assistant Professor
Dept. of Pharmaceutics
2017-2018
Dr. Vithalrao Vikhe Patil Foundation’s
College of Pharmacy, Ahmednagar. 1
Savitribai Phule Pune University, Pune

2. CONTENT
1) Introduction
2) Aim & Objectives of work
3) Plan of work
4) Drug Profile
5) Excipients Profile
6) Experimental work
7) Evaluation of Formulation
8) Summary
9) Conclusion
10) References 2

3. INTRODUCTION
Capsule:- A solid dosage form in which the drug is enclosed in a hard or soft soluble
container, usually a form of gelatin.
Capsules are generally of two types:-
Mini tablet:-
Soft gelatin Capsule Hard gelatin Capsule
3

4. Tooling used in compression of mini tablets:-
Advantages of capsule:-
 They may be used to mask the unpleasant taste, aromatic odour, or appearance of a drug.
 They allow powders to be dispensed in an uncompressed form, thus allowing for quicker
dissolution and absorption of the drug.
 They may be easier than tablets for some people to swallow.
 They can be make to alter the release rate of the drug.
4

5. Advantages of Mini tablets:-
 They have less risk of dose dumping.
 Mini tablets are easy to manufacture compared to pellets as they have equal dimensions, weight with
smooth regular surface.
 They can be produced in a reproducible and continuous way.
 Mini tablets are good coating substrates as they have excellent size uniformity, regular shape and as
smooth surface.
 They offer high drug loading, a wide range of release rate patterns, and also fine tuning of these
release rates.
 They offer high degree of dispersion in the GI tract, thus minimizing the risks of high local drug
concentrations.
Introduction to skeletal muscle disease:-
 A muscle relaxant is a drug which affects skeletal muscle function and decreases the muscle tone.
 They are used to alleviate symptoms such as muscle spasms, pain, and hyperreflexia.
 Muscle relaxants are of two major therapeutic groups: -Neuromuscular blockers & Spasmolytics.
 Spasmolytics are used to alleviate musculoskeletal pain, spasms and to reduce spasticity in a variety
of neurological conditions. They are of three types
1. Centrally acting
2. Directly acting
3. Miscellaneous
 Spasmolytic agents generally work by either enhancing the level of inhibition, or reducing the
level of excitation.
 In humans, GABA is directly responsible for the regulation of muscle tone.
5

6. Mechanism of drug released through capsule:-
 Inhalation of capsule
 Capsule dissolved & tablet is released
 Medium starts penetrating in to the matrix and wetting of the polymer takes place
 Expansion of the gel layer takes place with the formation of gel front
1. Soluble drug is released from the gel layer through diffusion
2. Insoluble drug is released from the gel layer through diffusion and errosion of the gel layer.
General process of Manufacturing of ER Capsule:-
Weighing & Sifting of all materials.
Wet Granulation.
Drying , Lubrication, tablet compression.
Applying coating & Non coating Strategy
Capsule Filling & sealing.
Packaging.
Formulation send for analysis.
6

7. AIM & OBJECTIVES OF WORK
Aim:-
The aim of the present work is to develop a matrix formulation and do the
evaluation tests for the same for an orally administrable extended release capsule of
Centrally acting Skeletal muscle relaxant by using release controlling polymers.
Objective:-
To analyse the API & various excipients before formulation.
To prepare stable formulation with acceptable process parameters.
To formulate extended release capsule by using controlled release polymer and to
achieve comparable dissolution profile with that of innovator formulation.
To Perform stability study on optimized formulation.
Application of statistical software for creation of Design space for the designed
formulation.
7

8. PLAN OF WORK
Selection of drug
Selection of excipients
Literature survey
Characterization
Characterization of API Innovator product dissolution
8

9. Characterization of drugs
UV analysis
Solubility analysis
Determination of melting
point
Infrared spectroscopy
Granulation
Formula optimization
Formulation of Tablets
BD,TD, CI& HR
PSD by malvern
method
Drug-excipients
compatibility study
BD,TD, CI& HR
PSD of
final batch
Evaluation of Tablets
Weight variation
HardnessThickness
Friability
9

10. Filling of tablet in capsule
sized 02
Content Uniformity
Packaging of capsules in
HDPE bottle
Consolation & report
writing
Stability & DOE study
Evaluation of capsules
Weight uniformity
Lock length
RS of final batch
In vitro dissolution
study
Assay of final batch
10

11. DRUG PROFILE
Sr no. Parameter Description
01 Name Of Drug X API
02 Class of Drug Skeletal Muscle Relaxant.
03 Solubility It is freely soluble in
water, sparingly soluble in
isopropanol & insoluble
in hydrocarbon solvents
04 Half life 18 hours
05 Bioavailability 33% to 55%
06 Assay % w/w 98.0-102.0%
07 Melting Point 216-218
08 Description Colour:- White
Odour:- Noxious
Taste:- Bitter
09 Molecular Formula C20H22ClN
10 Dose 15mg & 30mg ER
Capsule once a day
11

12. EXCIPIENTS PROFILE
Sr. No. Excipient Use
01 Methocel K100M CR Release controlling
polymer
02 Eudragit L100 55 Release controlling
polymer
03 Pharmatose 200M Diluent
04 Avicel PH102 Filler
05 Magnesium stearate Lubricant
06 Hydroxypropyl cellulose Release controlling
polymer
07 Ethocel -10FP Release controlling
polymer
08 PVP K-30 Binder
09 TEC Plasticizer
12

13. EXPERIMENTAL WORK
Preformulation study of API:-
1. Determination of Solubility X API
2. Melting Point Determination of X API.
3. Determination of λ max & Linearity study.
4. Bulk density, Tapped density, Hauser’s ratio, & Compressibility Index of X API.
5. Particle Size Distribution for API by Malvern sieve analyser.
6. FTIR of API & Optimized formulation.
7. Drug-excipient compatibility study
13

14. Evaluation test:-
For lubricated blends
Bulk density, Tapped density, Hauser’s ratio, Compressibility Index & Angle of Repose &
Particle Size Distribution by electromagnetic sieve shaker.
Tablet evaluation test
 Avg weight(mg)
 Thickness(mm)
 Friability(%)
 Hardness(N)
Capsules evaluation test
 Assay value(%)
 Avg.wt(mg)
 Lock length(mm)
 Weight uniformity
Drug release study
Stablity study
Moisture Content of Capsule
Related Substances by HPLC
DOE Study
14

15. Preparation ER capsule of SMR:-
Dispense each
ingredient
separately
Sifting through 40#
each ingredient
separately
Granulation using 2lt RMG(water
as binding agent)
Semi drying(FBD)
Sifting through
20#sieve
20#retained granules are
Milled(Quadroco mill-1.5G
screen)
Sifting through
20#sieve
Final Drying(FBD)
Addition of Lubricant
(60#passed) and Blending using
DCB
Compression into
tablets
Coating /Non coating
strategyFormulation design
15

16. Finalized/optimized formulation composition(Trial 07):-
Sr. No Ingredients mg/tab
1 X API
15.00
2 Hypromellose 2208(Methocel K100 MCR)
27.00
3 Eudragit L100 55
7.00
4 Lactose monohydrate
23.00
5 Avicel PH 102(MCC)
27.50
Purified water q.s
6 Magnesium stearate 0.50
Weight of core tablet 100.00 16

17. EVALUATION TEST
Preformulation study of X API:-
Determination of solubility:-
It is freely soluble in water and alcohol, sparingly soluble in isopropanol, and insoluble in
hydrocarbon solvents.
Melting Point of X API:- The Recorded melting point of API was 215°C.
UV of X API:-
The λ max of API is 291nm. 17

18. Linearity study:-
Conc.(µg/ml) Mean Abs
5 0.169
10 0.339
15 0.516
20 0.694
25 0.863
30 1.042
y = 0.0348x - 0.0042
R² = 0.9999
-0.2
0
0.2
0.4
0.6
0.8
1
1.2
0 5 10 15 20 25 30 35
Meanabsorbance
Concentration (µg/ml)
18

19. PSD of API by Malvern method:-
Conclusion:- API has 90% of the particle size below 14.054 µm
Determination of flow property of X API:-
Bulk density of API:- 0.191gm/ml.
Tapped density of API:-0.465gm/ml
Hausner’s ratio:- 2.387 which indicates very very poor flow property of the API
Carr’s Index:- 58.823% which indicates extremely poor flow property of the API.
19

20. FT-IR of API & Formulation:-
Sr. No IR Range(cm-1) Recorded
value(cm-1)
Functional
Group
1 3350-3250 3300 -N-C
2 2960-2850 2975 -C-H
3 2500-2300 2440 N≡C
4 1635-1600 1620 C=C
5 1425-1250 1487 C-N
Sr. No IR
Range(cm-1)
Recorded
value(cm-
1)
Functional
Group
1 3350-3250 3300 -N-C
2 2960-2850 2975 -C-H
3 2500-2300 2440 N≡C
4 1635-1600 1620 C=C
5 1425-1250 1487 C-N
6 1710-1690 1705 -C=O
7 3700-3500 3493 -OHFTIR of API
FTIR of Formulation
20

21. Drug-excipients compatibility study:-
Sr. No. Ingredients Ratio Physical
appearance
Open Vail
Physical
appearance
Closed Vail
Physical
appearance
1 Month
400C/75%RH
1 Month
400C/75%RH
01 API+Methocel
K100M CR
1:5 White NC NC
02 API+ Eudragit L-
100 55
1:2 White NC NC
03 API+ Avicel PH
102
1:5 White NC NC
04 API+ Lactose
Monohydrate
1:5 White NC NC
05 API+ Magnesium
Stearate
1:0.5 White NC NC
21

22. Evaluation Test:-
Evaluation Test of Lubricated blends:-
PSD of Finalized Formulation(Trial 08):-
The 90% of lubricated blend having the particle size less than or equal to 0.850mm which can be easily
passable through #20 ASTM sieve, this powder is called as Coarse Powder.
Trial No.
Bulk Density
(gm/ml)
Tapped
Density
(gm/ml)
Compressibility
Index (%)
Hausner’s
Ratio
Angle of
Repose
Trial 01 0.407 0.551 35.38 1.35 39.35
Trial 02 0.461 0.538 16.70 1.16 39.55
Trial 03 0.412 0.530 28.64 1.28 41.80
Trial 04 0.490 0.528 7.75 1.07 38.22
Trial 05 0.440 0.530 20.45 1.20 39.12
Trial 06 0.440 0.540 22.72 1.22 39.47
Trial 07 0.445 0.530 19.10 1.19 34.28
Trial 08 0.446 0.532 19.28 1.19 34.39
22

23. Tablet evaluation test:-
Trial No.
Avg. weight
(mg)
Thickness(mm) Friability(%) Hardness(N)
Trail 01 102.5 4.1 0.3 55
Trail 02 103.1 4.2 0.2 58
Trail 03 202.4 7.7 0.2 165
Trail 04 201.9 7.6 Nil 178
Trail 05 201.2 7.4 0.1 160
Trail 06 102.5 4.1 0.1 85
Trail 07 102.4 4.2 0.15 67
Trail 08 101.1 4.1 0.11 66
23

24. Capsules evaluation test:-
Content uniformity:- 85-115%
Weight uniformity:- 96-105mg.
Lock length(mm):- 18-22mm.
USP specification for drug release:-
Trail No. Assay value(%) Avg.wt(mg) Lock length(mm)
1 96.5 162.5 19.15±0.05
2 97.2 163.1 19.17±0.05
3 98.6 262.4 19.19±0.05
4 102.1 261.9 19.12±0.20
5 98.5 261.2 19.09±0.20
6 101.9 161.3 19.32±0.05
7 98.9 162.2 17.47±0.05
8 98.2 161.5 17.34±0.05
Time
Points(hrs)
USP
specification
2 NMT 40%
4 40-65%
8 60-85%
16 NLT 80%
24

25. Drug release of Formulation trials(In 0.1N HCL):-
Drug release of trials 07 & 08(In 4.5 & 6.8):-
Time
points(
hrs)
Refere
nce
Sampl
e
Trial
01
Trial
02
Trial
03
Trial
04
Trial
05
Trial
06
Trial
07
Trial
08
2 31 0 63 22 44 33 36 31 35
4 54 1 102 35 54 43 60 51 57
8 70 1 - 58 86 66 89 77 82
16 84 - - 80 - 89 - 96 95
Time
points(hrs)
Trial 07 Trial 08
RLD
4.5
Samp.
4.5
RLD
6.8
Samp
. 6.8
RLD
4.5
Samp.
4.5
RL
D
6.8
Samp.
6.8
2 33 31 27 24 33 34 27 27
4 57 54 51 37 57 58 51 41
8 74 78 70 60 74 85 70 64
16 86 93 82 87 86 96 82 95
25

26. Graphical representation of optimized batch(Trial 07):-
Trial 07 drug release in 0.1N HCL
Trial 07 drug release in 4.5 & 6.8 buffer
0
20
40
60
80
100
120
0 2 4 6 8 10 12 14 16 18
Cumulative%drugreleased
Timr(hrs)
Reference Sample
0.1N HCl
Trial7 0.1N HCl
0
20
40
60
80
100
0 2 4 6 8 10 12 14 16 18
Cumulative%drugreleased
Time(hrs)
Reference sample
6.8pH PB
Trial7 6.8pH PB
Reference sample
4.5pH AB
Trial7 4.5pH AB
26

27. 27
0
20
40
60
80
100
0 2 4 6 8 10 12 14 16 18
Cumulative%drugreleased
Time(hrs)
Reference Sample
Trial8
0
20
40
60
80
100
120
0 2 4 6 8 10 12 14 16 18
Cumulative%drugreleased
Time(hrs)
Reference
sample 6.8pH PB
Trial8 6.8pH PB
Reference
sample 4.5pH AB
Trial8 4.5pH AB
Trial 08 drug release in 0.1N HCL
Trial 08 drug release in 4.5 & 6.8 buffer
Graphical representation of Reprodiciable batch(Trial 08)

28. Stability study:-
With 3 gm dessicant Without 3 gm dessicant
Time
Points
(hrs)
1
Month
2
Month
3
Month
1
Month
2
Month
3
Month
2 27 27 27 23 19 14
4 47 43 45 43 37 34
8 73 74 76 65 58 59
16 91 92 92 88 87 88
With 3 gm dessicant
0
20
40
60
80
100
120
0 5 10 15 20 25 30
cumulative%drug
released
Time(hrs)
Initial
1M
2M
3M
0
20
40
60
80
100
120
0 5 10 15 20 25 30
Cumulative%drugreleased
Time(hrs)
Initial
1M
2M
3M
Without 3 gm dessicant
28

29. Assay results for stability sample:-
Moisture Content of Capsule result RS by HPLC:-
of stability sample
(By using water by Kf method):-
Parameter
Condition 40°C/ 75%RH
(without desiccant)
Condition 40°C/
75%RH
(with desiccant)
Assay (%
w/w)
Months Months
Initial
1M 2M 3M
Initial
1M 2M 3M
99.9 98 96 95.5 99.6 97.6 97.3 97.1
Trial
Batch No.
07 08
Moisture
content
1.75% 1.8%
Name of impurity Batch No.:- 08
Impurity B 0.000
Amitriptyline 0.000
Impurity A 0.000
Highest Unknown 0.048
Total Unknown 0.056
Total Related
Substance 0.056
29

30. Formulation optimization and creation of Design space:-
Run order for the factorial design:-
Response Optimization:-
Run order/Trial
No.
A B
1 + -
2 - -
3 + +
4 0 0
5 - +
6 0 0
Goal Lower Target Upper
2hrs Minimum 30 30 40
4hrs Target 40 50 65
8hrs Target 60 80 85
Predicted
responses
Desirability
2hrs 30.0833 0.991667
4hrs 50.75 0.95
8hrs 77.3333 0.866667
30

31. Cur
High
Low0.93465
D
Optimal
d = 0.99167
Minimum
2hrs
y = 30.0833
d = 0.95000
Targ: 50.0
4hrs
y = 50.750
d = 0.86667
Targ: 80.0
8hrs
y = 77.3333
0.93465
Desirability
Composite
10.0
18.0
50.0
58.0
EudragitMethocel
[58.0] [18.0]
Graph showing desirability for the responses:-
31

32. Methocel K100M CR
EudragitL100-55
585756555453525150
18
17
16
15
14
13
12
11
10
>
–
–
–
–
< 31
31 32
32 33
33 34
34 35
35
2hrs
2hrs drug release
17.5
15.030.0
31.5
33.0
12.5
34.5
50.0
52.5 10.055.0
57.5
2hrs
Eudragit L100-55
Methocel K100M CR
2hrs drug release
Drug release at 2hrs:-
Surface plot
Counter plot
32

33. Methocel K100M CR
EudragitL100-55
585756555453525150
18
17
16
15
14
13
12
11
10
>
–
–
–
–
–
–
< 50
50 51
51 52
52 53
53 54
54 55
55 56
56
4hrs
4hrs drug release
17.5
15.0
50
52
54
12.5
50.0
56
52.5 10.055.0
57.5
4hrs
Eudragit L100-55
Methocel K100M CR
4hrs drug release
Drug release at 4hrs:-
Counter plot
Surface plot
33

34. Methocel K100M CR
EudragitL100-55
585756555453525150
18
17
16
15
14
13
12
11
10
>
–
–
–
–
< 76
76 78
78 80
80 82
82 84
84
8hrs
8hrs drug release
17.5
15.0
75.0
77.5
80.0
82.5
12.5
50.0
52.5 10.055.0
57.5
8hrs
Eudragit L100-55
Methocel K100M CR
8hrs drug release
Drug release at 8hrs:-
Counter plot
Surface plot
34

35. Overlaid plot:-
Methocel K100M CR
EudragitL100-55
585756555453525150
18
17
16
15
14
13
12
11
10
30
35
2hrs
50
60
4hrs
80
85
8hrs
overlaid plot
Methocel K100M CR = 54.0087
Eudragit L100-55 = 14.0747
2hrs = 32.8248
4hrs = 53.4800
8hrs = 80.8070
35

36. SUMMARY
1.The Present investigation is to develop oral extended release capsules containing centrally acting
skeletal muscle relaxant which is therapeutically and pharmaceutically equivalent to Reference Listed
Drug (RLD) from Orange book.
2.Avicel PH-102 is added to increase the flow properties. Lactose monohydrate is taken as a diluent.
3.Firstly the matrix tablet contained Methocel K15M CR as release controlling agent. Further the matrix
tablet was coated with Ethylcellulose-10FP. Two trial batches were taken with change in coating solution
composition varying Ethylcellulose-10FP concentration in it. When compared with the Reference sample
dissolution profile the trials batches release profile was not matching.
4.A change in the strategy of the formulation of Methocel K100M CR as release controlling polymer in
the matrix tablet & Eudragit L100-55 was included in the later formulation trials which controlled the
drug release from the dosage form in the initial hours of dissolution.
5.Final formulation which was optimized contained One Tablet in one Capsule for 15mg & two tablets in
the one capsule for 30mg with each tablet weighing 100mg approximately.
6.The capsules were charged on accelerated stability studies at 40±20c/75%±5 %RH in 60CC HDPE thick
wall bottles (30 counts) with a child resistant cap. The pack contained one Monodesiccant. There were no
significant changes observed.
7.The API and excipients used did not show any incompatibilities as interpreted from drug excipients
compatibility studies. Besides that the formulation was found to pass various preformulation tests.
36

37. CONCLUSION
1.IR and Compatibility study shows that there is compatibility between drug and excipients.
2.From the BD, TD, CI & HR Study show the low flow property of API. Hence wet granulation technique
is used to increase the flow property.
3.In the Trial No. 07 the desired release profile was obtained by optimizing amount of Methocel K100M
CR & Eudragit L100 55. From the in vitro drug release study, it was inferred that drug release increased
with the amount of Release Controlling Polymers and filler, lubricant.
4.In the formulation (batch 07) containing 15mg (15%) of Skeletal muscle relaxants API and 34%
Release Controlling Polymers was found to deliver 16hrs drug release.
5.The result of stability study result is found Satisfactory as per USP Requirement.
6.API is used as a centrally acting skeletal muscle relaxants agent, for oral administration in the treatment
of Skeletal muscle disease, smooth muscles of heart, migraine, low back pain, pain in joints etc. It has a
half life of 18 hours. When dose is missing it may causes myocardial infarction, and patients with
arrhythmias, heart block or conduction disturbances, or congestive heart failure so extended release
tablets of Centrally acting skeletal muscle relaxant & filled into capsules.
7.To reduce the frequency of administration, to improve patient compliance & to avoid odour & taste of
API, an extended release Capsule formulation of Skeletal muscle relaxants is desirable. 37

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Methyl Cellulose as Rate-controlling Polymer, Journal of Young Pharmacists,Vol 4
/ No 1.
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Technology, International Journal of Pharmaceuticaland Chemical Sciences Apr –
Jun 2012 Vol. 1 (2)
Hand Book of Excipients, 6thEdition.
38

39. LakshmanaPrabu S*, Sharvanan SP, Aravindan S, Bhuvaneswari A and
Manikandan V, Nanoemulgel for Transdermal Delivery of Cyclobenzaprine
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substance and products (Availableonline:http://http://www.ich.org).
39

40. Thank You…
40