FORMULATION AND EVALUATION OF BI-LAYER SUSTAINED RELEASE TABLET OF AZITHROMYCIN AND DOXYCYCLINE DRUG. Bilayer tablets, sometimes called double-layer tablets, are a newer technology for the development of controlled release formulation. They have a combination of two or more active pharmaceutical ingredients in a single dosage form. Nowadays, the use of bi-layered tablets is growing.

1. FORMULATION AND EVALUATION OF BI-LAYER SUSTAINED
RELEASE TABLET OF AZITHROMYCINAND DOXYCYCLINE
DRUG.
GUIDED BY –
PROF. P.V. VEERKAR
M.PHARM
PREPARED BY-
MR.ADINATH
SANGALE
M.PHARM SEM-1
PHARMACEUTICAL
QUALITYASSURANCE
DEPARTMENT
ROLLNO. 10
MULAEDUCATION SOCEITY COLLEGE OF PHARMACY, SONAI
AHMEDNAGAR (2021-2022)

2. CONTENTS :
 Introduction.
 Literature Review
 Need of Work.
 Aim and objective.
 Plan of Work.
 Material and method
 Evaluation Parameters.
 Result and Disscusion.
 Conclusion.
 Reference.
1

3. INTRODUCTION :
 Bilayer tablets, sometimes called double-layer tablets, are a
newer technology for the development of controlled release
formulation. They have a combination of two or more active
pharmaceutical ingredients in a single dosage form.
Nowadays, the use of bi-layered tablets is growing.
 the medicines which consist of two same or different drugs
combined in a single dose for effective treatment of the
disease.
 Bi-layer tablets are developed to achieve controlled delivery
of different drugs with pre-defined release profiles.
 Bi-layer tablets are presently being developed by several
pharmaceutical companies.
2

4.  Patent expansion, therapeutic, marketing to name a
few, for a multitude of purposes.
 Bilayer tablets have certain problems such as layer
separation, compression, colour shading. There are
also various methods to minimize or solve these
problems.
3

5. Sustained Release Tablets:
4
 Sustained-release tablets are manufactured to be more potent
but dissolve slowly so they release small amounts of a
medication into a patient's system over an extended period of
time. Controlled release technologies allow patients and
physicians to be in better control of patient health.
 Sustained-release (SR) drugs maintain drug release over a
sustained period but not at a constant rate.
 Reduces the number of doses which lowers expenses and
improves patient compliance, especially for chronic diseases.
Decreases side effects.

6. COVID-19 :
5
 Covid-19 is a pandemic disease with high mortality which is
caused by the rapid spread of the Severe Acute Respiratory
Syndrome SARS-COV-2. It appeared for the first time in
Wuhan, China, in December 2019, WHO later announced that
the disease had become a global pandemic When this research
was prepared in early July 2020, about half a million deaths
were reported; out of approximately 11 million confirmed
cases of COVID-19 worldwide .

7. Secondary infection :
6
 Viral pneumonia increases the risk of bacterial co-infection which raises the
severity and mortality of the disease.
 2020 reported that about 50% of patients who are died after hospitalization
due to COVID-19 had secondary bacterial infections. Studies indicated that
10-30% of hospitalized patients with severe COVID-19 commonly suffer
secondary infections.

8. Role of antibiotics in COVID-19 :
European Respiratory Society China, Germany (Indian MOH (MOHFW-Guidlines -India,
2020). Turkish (and Egyptian (MOHP.EG, 2020) (guidelines described the importance of
antibiotics in the management of secondary infection associated with COVID-19. Some other
guidelines didn't mention the role of antibiotics, examples include web published guidelines
Australia and the SaudiArabia Ministry of Health.
This review aims to recall experience regarding the role of antibiotics in previous viral
pneumonia pandemics and to provide a pharmacological basis of the potential role of
specified antibiotics Doxycycline (DOX) and Azithromycin (AZ) to improve clinical
outcomes of management of COVID -19. SARS-CoV-2, Viral pneumonia, Antibiotics,
antiviral drugs, immunomodulation, secondary infection, Antibiotics- Macrolide
Azithromycin, Tetracycline- Doxycycline Use. 7

9.  The current review provided the detailed antiviral, immunomodulatory effect,
unique pharmacokinetic profile of two antibiotics namely azithromycin and
doxycycline. It summarizes current clinical trials and concerns regarding
safety issues of these drugs.
 Azithromycin has excellent lung tissue penetration, broad antibacterial
effectiveness, and potential antiviral activity against COVID-19.
 In limited clinical trials, it also showed efficacy when paired with other
antiviral medications, however many clinicians are concerned about
cardiovascular risk in susceptible patients.
 Doxycycline plays an important role in the treatment of pneumonia. It has a
number of advantages, including cardiac safety, easy access to lung tissue,
antiviral potential, and immunomodulation effects through a variety of routes.
The pharmacological characteristics of these medicines raise the possibility of
additional research into their use in the treatment of COVID-19.
8

10. Literature Review :
Ahmed S. Ali, Mai A. ASattar. (2021) - A novel corona virus SARS-CoV-7 has
led to an outbreak of the highly infectious pan demic COVID-19 complicated viral
pneumonia. Patients with risk factors frequently develop sec on dary infections
where the role of appropriate antibiotics is mandatory. However, the efforts of
drug repurposing lead to recognizing the role of certain antibiotics beyond the
management of infection. The current review provided the detailed antiviral,
immunomodulatory effect, unique pharmacokinetic profile of two antibiotics
namely azithromycin (AZ) and doxycycline (DOX).
Usha Yendrapalli. (202112 patients (9.5%) required oxygen of 1-2 Lat discharge. 80.9% of
patients have been discharged home or inpatient rehabilitation. 2021 Published by Elsevier
Ltd on behalf of King Saud BinAbdulaziz University for Health Sciences.
Nobuaki Mori (2020)- specific therapy is available for COVID-19. We report the
effectiveness and adverse effects of triple therapy with hydroxychloroquine,
azithromycin.
9

11. Muneeba Akhtar (2020)- Bilayer tablets are the medicines which consist of two
same or different drugs combined in a single dose for effective treatment of the
disease. The aim of this review is to reveal the challenges that appear during the
preparation of bilayer tablets, and also propose solutions for these challenges.
Nobuaki Mori (2020)- specific therapy is available for COVID-19. We report the
effectiveness and adverse effects of triple therapy with hydroxychloroquine,
azithromycin.
10

12. NEED OF WORK :
Bi-Layer sustained release tablet and a mixture of drugs that are two
different drugs are effective combination in one dose.
 To overcome following the problems of drugs and diseases:-
 Future Prospects Benefits of CombiningAZI and DOXY is more
advantageous.
 avoiding multiple doses in a day.
 To avoid the risk of corona and pneumonia.
 The mixture of one tablet works on many diseases. Such as Covid-19,
pneumonia, nongonococcal uthirites.
 Future Prospects Benefits ofAzi + Doxy - Combining doxy and azi is
more advantageous.
 This is because when the two medications are taken together, they
work better.At the same time
11

13. From literature survey, it was found that not a single work has been done on
the combination of these two drugs. Majority of the work has been done on
each drug individually or with these drugs in combinations with the drugs of
their own categories only. However literature survey did not indicate the
availability of any research article related to combination of these two drugs in
combination and in the form of bilayer tablets.
12

14. AIM AND OBJECTIVE OF WORK :
13
Formulation, Evaluation and Development of Sustained
Release Bi-layer tablet of combination Azithromycin and
Doxycycline drugs.
Azithromycin has excellent lung tissue penetration, broad antibacterial
effectiveness, and potential antiviral activity against COVID-19.
Doxycycline plays an important role in the treatment of pneumonia. It has a
number of advantages, including cardiac safety, easy access to lung tissue,
antiviral potential, and immunomodulation effects through a variety of routes.
The pharmacological characteristics of these medicines raise the possibility of
additional research into their use in the treatment of COVID-19.

15. The Main Objectives of Present Work Are:
14
 Formulation of a bilayer tablet for convenience and ease of
administration.Accuracy in Dosing Size.
 Avoiding multiple tablets in a day for the patients for two diseases.
 Avoiding dose dumping and thus reducing toxicity levels in
patients.
 Longer Duration of action and efficacy.
 Decrease in cost i.e Cost effective.
 Attractive colour in one layer to differentiate between two layers
and also to increase patient acceptability.

16. Plan of Work
PLAN OF WORK
Literature survey
Selection of drug
Selection of excipients
Preformulation study
API
Preformulation study
of Excipients
15

17. Solubility, melting point, UV,
pH, maximum wavelength
Physical evaluation of
excipients
Formulation SR release tablet by suitable
method
Bulk and tapped
density
Angle of repose
Hausner’s ratio
and car’s index
Drug content
In-Vitro drug release
study
16

18. 2) Doxycycline
 API- 1)Azithromycin
 Excipients-
Croscarmellose.
Sodium starch glycolate.
Talcum.
PVP K 30.
Aerosil.
Microcrystalline cellulose.
Magnesium stearate.
I. Disintegrating-
II. Superdisintegrant-
III. Absorb moisture-
IV. Good adhesive properties-
V. Increased hardness –
VI. Binder/Diluent -
VII.Flow agent-
VIII.
IX.
Excellent compressibility properties- Lactose.
Binder or matrix former- CMC/Carboxymethel cellulose.
MATERIALS AND METHOD :
17

19. Appearance and color-
18
1) Azithromycin – White crystalline powder, odourless powder.
2) Doxycycline – light-yellow crystalline powder, odorless powder.
Melting point detection-
The melting point ofAzithromycin and Doxycycline is matched with standard melting point.
Sr.
No. Melting Point Range
AZITHROMYCIN
(API)
DOXYCYCLINE
(API)
1. As per Literature 1130-1150 C 212-219 0 C
2. Practical 1150 C 2140 C

20. Ultraviolet Absorbance Spectrum- Azithromycin
190 400
1.3
1
Abs
0.5
0.1
300
Wavelength [nm]
λmax of azithromycin-210 nm
19

21. Calibration Curve of Azithromycin in Methanol at various
concentration-
20
Sr.
No.
Concentration
(µg/ml)
Absorbance
1. 0 0
2. 5 0.03245
3. 10 0.06757
4. 15 0.102797
5. 20 0.136824
6. 25 0.175807

22. Standard curve of of Azithromycin in Methanol
y = 0.007x + 0.0018
R² = 0.9994
21
0.2
0.18
0.16
0.14
0.12
0.1
0.08
0.06
0.04
0.02
0
-0.02
0 5 10 15 20 25 30
Chart Title
Sr.
No.
Solvent Equation R2
1. Methanol y = 0.007x + 0.0018 0.9994
a
b
s
conc

23. Ultraviolet Absorbance Spectrum- Doxycycline
200 400
350
1.7
1.5
1
Abs
0.5
0
Wavelength [nm]
λmax of Doxycycline -275 nm
22
250 Conc3
.00

24. Sr. No.
Concentration
(µgm/ml)
Absorbance
1 0 0
2 2 0.4035
3 4 0.7595
4 6 1.0526
5 8 1.3511
6 10 1.7153
23
Calibration Curve of Doxycycline in Methanol at various concentration-

25. Standard curve of Doxycycline in Methanol-
y = 0.6801x + 0.0318
R² = 0.9988
24
1.8
1.6
1.4
1.2
1
0.8
0.6
0.4
0.2
0
2
0 0.5 1 1.5 2 2.5 3
Chart Title
a
b
s
Conc.
Sr.
no
Solvent Equation R2
1. Methanol y = 0.6801x + 0.0318 R² = 0.9988

26. Infrared Spectrum of Azithromycin-
Sr.
No.
Inference Wave Number (cm-1)
1. OH stretching (intermolecular hydrogen
bonding)
3436.53
2. C-H Stretching vibration 2971.77
3. C= O carbonyl ester Stretching 1720.19
4. CH3 -O 1456.96
5. CH2-O 1377.89
6. C-O-C 1050.05
25

27. Infrared Spectrum of Doxycycline -
26

28. IR peak value of Azithromycin and Doxycycline Mixture
with Polymers :
Types of Bonds Wave Number /cm -1
Found
N-H Stretching 3456.78
C-H Stretching (Methyl) 2970.8
C-H Stretching Vibration of (aromaticring) 3114.47
C=O Stretching Vibration of Amide Moiety 1650.77
Aliphatic C-H Stretch 2962.13
CH2 (Bending) 1461.78
C=C Stretching/bending 1599.66
COOH bending 1381.75
Disubstituted benzene 1696.09
27

29. Differential Scanning Calorimetry (DSC):
28
As per literature the thermogram of Azithromycin was observed at 115°C.
The above DSC thermogram is observed at 115°C which is similar to the
literature. . The Azitromycin and Doxycycline bilayer Tablet Formulation
exhibited double, sharp endothermic peaks at 214.43°C, 155.73°C and
170.91°C.

30. Azithromycin and Doxycycline DSC thermogram was evaluated and it is concluded
that, there no such
interference occurs in between drug and excipient. The thermogram of Azithromycin
and Doxycycline ,
29
Azithromycin and Doxycycline with polymer given in Figure.

31. Compositions of Bilayer Tablets Sustained Release Layer of Azithromycin:-
Sr.No Ingredient F1(mg) F2(mg) F3(mg) F4(mg) F5(mg)
1 Azithromycin 250 250 250 250 250
2 Carboxymethylcellulose/CMC 6 6 9 9 6
3 PVP K30 10 11 12 8 5
4 Starch 32 30 25 30 28
5 Lactose 10 10 12 9 10
6 Mannitol 8 10 8 10 14
7 Magnesium sterate 6 4 6 4 7
8 Talcum 3 4 3 5 5
9 p.water Q.S Q.S Q.S Q.S Q.S
Total weighat 325 325 325 325 325

32. Compositions of Bilayer Tablets Sustained Release Layer of Doxycycline:
Sr.No Ingredient F1(mg) F2(mg) F3(mg) F4(mg) F5(mg)
1 Doxycycline 100 100 100 100 100
2 Carboxymethylcellulose /CMC 10 10 8 9 9
3 PVP K30 6 11 2 4 11
4 Starch 26 24 25 25 26
5 Lactose 9 7 8 6 8
6 Magnesium sterate 9 9 6 9 6
7 Talcum 15 14 15 15 15
8 p.water Q.S Q.S Q.S Q.S Q.S
Total weighat 175 175 175 175 175

33. Precompression studies- Azithromycin :
30
Formulation
Code
Bulk
Density
Tapped
Density
Carr’s
Index (%)
Housner’s
Ratio (%)
Angle of
Repose
(Degree)
R1. 0.06944 0.08333 20 1.200 37.99
R2. 0.06957 0.08346 19 1.199 37.89
R3. 0.06933 0.08311 20 1.198 37.81
R4. 0.06947 0.08341 20 1.200 37.55
R5. 0.06940 0.08344 19 1.202 37.99

34. Precompression studies- Doxycycline
31
Formulation
Code
Bulk
Density
Tapped
Density
Carr’s
Index (%)
Housner’s
Ratio (%)
Angle of
Repose
(Degree)
F1. 0.072 0.097 25.77 1.3472 36.99
F2. 0.072 0.097 25.77 1.3472 36.89
F3. 0.072 0.098 26.53 1.3611 37.96
F4. 0.073 0.097 25.77 1.3287 37.54
F5. 0.071 0.096 26.04 1.3521 37.95

35. Disintegration time-
32
Formulation Code Disintegrating time (min)
R3 120

36. 36
33
Time
Min&
Hr.
% Of drug release
R1 R2 R3 R4 R5
45 m 6.21 6.14 7.02 6.22 7.00
1 9.00 8.00 9.00 9.21 8.99
2 12.78 11.08 12.15 11.25 9.66
3 16.32 15.02 16.98 15.36 12.22
4 20.2 18.2 21.28 20.00 16.00
5 24.55 21.2 25.47 24.23 18.12
6 27.93 24.03 28.93 28.32 19.21
7 29.87 28.07 29.75 29.32 23.00
8 32.55 29.15 33.53 31.22 26.00
9 34.04 30.14 35.08 32.56 28.21
10 36.33 32.33 38.32 33.4 29.32
11 38.12 33.12 39.12 35.85 30.00
Time
Hr.
% Of drug release
12 39.56 36.26 40.56 40.00 38.00
13 40.00 38.00 41.23 41.21 39.00
14 41.23 40.83 42.45 42.21 40.78
15 42.55 41.50 43.23 43.25 42.1
16 43.00 42.00 44.00 44.23 43.26
17 44.21 43.20 45.30 45.21 44.23
18 45.31 44.30 46.12 46.32 45.26
19 46.31 45.85 47.00 47.21 45.99
20 47.56 46.76 48.28 48.2 46.88
21 48.22 47.22 49.95 49.25 47.12
22 49.14 48.18 50.00 50.21 48.12
In-Vitro Dissolution profile of SR- Azithromycin

37. 3
34
Time
Hr.
% Of drug release
R1 R2 R3 R4 R5
23 50.0 49.55 51.66 51.11 49.55
24 51.22 50.00 52.13 52.00 50.36
25 52.31 51.20 53.22 53.14 51.24
26 53.12 52.00 54.25 54.21 52.21
27 54.12 53.45 55.36 55.21 53.26
28 55.23 54.65 56.85 56.85 54.21
29 56.12 55.14 57.36 57.33 55.23
30 57.41 56.2 58.17 58.9 56.10
31 58.22 57.21 59.39 59.36 57.4
32 59.00 58.36 60.22 60.21 58.58
33 60.03 59.12 61.23 61.25 61.02
34 61.00 60.12 62.99 62.35 62.05
35 62.00 61.12 63.45 63.25 63.00
Time
Hr.
% Of drug release
36 63.00 62.21 64.22 64.41 64.23
37 64.55 63.14 65.22 65.23 65.26
38 65.9 64.75 66.32 66.10 66.32
39 66.2 65.23 67.65 67.22 67.25
40 67.00 66.53 68.25 68.32 68.32
41 68.12 67.53 69.22 69.32 69.32
42 69.12 68.22 70.21 70.25 70.21
43 70.00 69.32 71.25 71.24 71.51
44 71.12 70.00 72.56 72.27 72.32
45 72.21 71.56 73.99 73.29 73.56
46 73.58 72.23 74.65 74.56 74.21
47 74.21 73.5 75.25 75.00 75.09
48 75.00 74.00 76.35 76.32 76.77 7

38. Dissolution profile-Azithromycin
4.5
4
3.5
3
2.5
2
1.5
1
0.5
0
0 500 1000 1500 2000 2500 3000 3500 4000 4500
In-Vitro Dissolution profile
Series1 Series3 Series4 Series5
36
%
OF
DRUG
RELEASE
Series2
TIME

39. 37
in-Vitro Dissolution profile of SR- Doxycycline
Time
Hr.
% Of drug release
F1 F2 F3 F4 F5
0 0 0 0 0 0
1 0.99 0.86 1.10 0.92 0.90
2 5.4 4.9 10.98 0.96 0.93
3 9.5 9.00 16.79 1.02 1.00
4 14.8 13.2 21.14 6.3 5.3
5 18.19 17.3 26.12 11.04 10.02
6 22.00 19.22 30.82 17.43 14.12
7 27.21 27.18 34.00 22.21 18.19
8 32.56 32.00 38.52 27.63 23.00
9 37.44 36.00 42.11 32.37 28.56
10 42.11 40.00 46.23 37.54 33.88
Time
Hr.
% Of drug release
11 46.11 46.00 50.43 38.44 38.38
12 50.88 49.99 54.14 42.00 43.00
13 55.17 55.17 59.49 46.32 48.56
14 59.41 59.02 65.22 51.02 52.00
15 63.00 63.04 71.00 56.11 57.26
16 68.88 68.33 84.55 60.02 62.14
17 74.22 74.11 80.46 65.23 67.25
18 80.1 79.00 85.74 69.19 72.35
19 85.22 84.13 89.03 73.99 77.56
20 92.99 86.33 94.22 78.99 83.56

40. Dissolution profile-Doxycycline
0.86
0.84
0.82
0.8
0.78
0.76
0.74
0.72
0.88
-5 0 5 10 15 20 25
In-Vitro Dissolution profile
% Drug Release of Doxycycline
Series1 Series2 Series3 Series4 Series5
TIME
38
%
OF
DRUG
RELEASE

41. Stability study-
39
Formulation
Number.
Friability Hardness
(Kg/cm2)
% Drug release In-Vitro
Disintegration
time (min)
R3 0.522±0.028 5.7±0.10 95.10±0.05 122

42. CONCLUSION :
40
Sustained release Tablet (SR) of (AZI-DOX) were formulated successfully with desired
characteristics; disintegrated rapidly.
Prepared SR will provide Rapid onset of action.
Prepared SR will enhanced the patients convenience and Patients compliance.
The sustained-release tablet works at the right time.
Prepared SR is shown better andAdvanced formulation than Marketed tablet.

43. REFERENCES :
41
• 1) formulation development and in-vitro evaluation of double layer tablet of sustained release (s.r.)
flurbiprofen and immediate release doxycycline.
international journal of pharmaceutical sciences and research
IJPSR (2017), Volume 8, Issue 9
http://dx.doi.org/10.13040/UPSR.0975-8232.8 (9).3978-85
• 2) Preparation and evaluation of sustained-release azithromycin tablets in vitro and in vivo
Sustained-release tabletAzithromycinPharmacokineticsUPLC-MS-MS
journal homepage: http://ees.elsevier.com/ajps/default.asp
• 3) Design and Development of Bi-layered Sustained ReleaseAzithromycin Tablets
(Received: December 2, 2016;Accepted: December 18, 2016; Published (web): December 27,
2016)
• 4) Development and evaluation of bilayer tablets of combination of antibiotics for the treatment of
sexually transmitted disease

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december 2019 available online 8 august 2020.562-564
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46. 45