Development and in-vitro characterization of abacavir and zidovudine tablet in combination

1. Development and in-vitro characterization of
abacavir and zidovudine tablet in
combination
JOGINPALLY B. R. PHARMACY COLLEGE
YENKAPALLY, MOINABAD.
BY
B.SATYA DEVI
(12DQ1S0302)
UNDER THE GUIDANCE OF
Mr. M. Srinivas
M.Pharm
Department of Pharmaceutics

2. CONTENTS:
➢ INTRODUCTION
➢ REVIEW OF LITERATURE
➢ AIM & OBJECTIVE
➢ PLAN OF WORK
➢ DRUG PROFILE
➢ EXCEPIENTS PROFILE
➢ MATERIALS AND EQTIPMENTS
➢ METHODOLOGY
➢ RESULTS & DISCUSSION
➢ SUMMARY & CONCLUSION
➢ REFERENCES

3. INTRODUCTION
➢ The oral route of drug administra on is the most
important route of administering drugs for systemic effect.
About 90% of drugs used to produce systemic effects are
administered by oral route. HIV weakens the body's
immune system and reduces the body's ability to fight
infec ons.
➢ An -HIV medicines do not kill the virus but they slow
down or stop the HIV virus from making copies of it-self
➢ An -HIV medicines are most effec ve when taken in
combina on with other an -HIV-medicines. Combina on
therapy reduces the chances of the virus becoming
resistant to a single medicine and also produces synergis c
ac vity. Resistance to medicines makes HIV treatment
more difficult.

4. ADVANTAGES
➢ They are unit dosage forms, they offers greatest
capabili es of all oral dosage forms for the greatest dose
precision and the least variability
➢ Direct compression is less me consuming , economical ,
easy.
➢ Creates mul ple obstacles to HIV replica on
➢ Keeps off springs low
➢ Decrease viral load
➢ Poten ate synergis c ac vity with one another
➢ Reduces individual medica ons
➢ Reduce possibility of superior muta ons

5. LIMITATIONS:
■ Time of ini a on
■ Dose recommended
■ Lacta on
■ Recommended only when the CD4 cells are highly a acked.
■ High doses –increased weight-important for HIV pa ent to engage in
some physical exercises.

6. MECHANISM OF ACTION
NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITORS

7. RIVIEW OF LITERATURE
NAME
OF SCIENTIST
YEAR WORK
Vikramjith singh 2012 Study on tablets containing Zidovudine and
lamivudine
D.Varun 2011 Controlled release tablets of abacavir with different
polymers
Srikanth thota 2011 Immediate release tablets of
lamivudine,zidovudine,nevirapine-HAART
Kayitare E 2009 Fixed dose combina on of zidovudine and
lamivudine in paediatric use
Punna rao ravi 2008 Oral release tablets of zidovudine
Navarrete MS 1998 Combina on of two NRTIs

8. Aim & objective
AIM:
The main aim is to develop and evaluate immediate release tablets
of abacavir and zidovudine with different composi ons of common
excipients which will meet the standards to that of the reference product
with the subsequent achievement of In-vitro correla on with the reference
product.
OBJECTIVE:
The main objec ve of this work is to formulate conven onal release
oral solid dosage form of Abacavir and Zidovudine which is considered to
be stable.
➢ The developed tablets were evaluated for various compression
characteris cs like, weight varia on, friability, hardness, diameter and
thickness etc.
➢ To check drug excipients compa bility by using FTIR.
➢ To ascertain the release mechanics and kine cs of drug release from
tablets.
➢ To perform accelerated stability studies as per ICH guidelines.

9. PLAN OF WORK
➢ Selec on of drugs and excepients sutable for combina on
➢ Conduct Preformula on studies such as Bulk density, Tapped
density, Compressibility index, Hausner’s ra o and Angle of repose
on excipients and drug.
➢ Evaluate the formulated tablets according to the pharmacopoeial
standards by evalua ng the formulated tablets for Physical
Appearance, Hardness, Weight Varia ons, Friability, Thickness,
Disintegra on, Dissolu on, Drug content.
➢ Conduct compara ve release studies with that of the marketed
products and selec ng the best formula on
➢ Evaluate the mechanics and release kine cs of drug from the
prepared tablets.
➢ Arrive at on op mized formula on of abacavir and zidovudine tablet
compara ve to marketed immediate release products.
➢ Conduct drug and excipients compa bility using FTIR.
➢ Perform accelerated stability studies according to standards.

10. Drug profile
Name of Drug Abacavir (BCS class-3)
Chemical name {(1S,
4R)-4-[2-amino-6-(cyclopropylamino)-9H-purin-9-yl]cyclo
pent-2-en-1-yl}methanol
Molecular formula C14H18N6O
Molecular weight 286.332 g/mol
Category An Reteroviral
Description White to almost white powder.
solubility Freely soluble in water.
dosage The recommended oral dose of abacavir tablet for
adults is 600 mg daily, administered as either 300 mg
twice daily or 600 mg once daily.

11. Mechanism of abacavir:
Slows down the production of reverse transcriptase enzyme decreases the
viral load and increases CD4+ cell count in HIV patients
Absorption Rapid and extensive after
oral administration
Bioavailability (83% bioavailability, tablet).
Metabolism Hepatic, by alcohol
dehydrogenase and
glucuronosyltransferase
Elimination Urine and fecal routes
Half life 1.54 ± 0.63 hours
Plasma protein binding App 50%

12. Drug profile
Name of Drug Zidovudine (BCS class-1)
Chemical name 1-[(2R,4S,5S)-4-Azido-5-(hydroxymethyl)oxolan-2-yl]-5-
methylpyrimidine-2,4-dione
Molecular formula C10H13N5O4
Molecular weight 267.242 g/mol
Category An reteroviral
Description Mostly white in colour
solubility Soluble in water to about 20 mg/ml
dosage For the treatment of HIV infection the recommended
oral dose for adults is 100 mg every 4 hours.

13. Mechanism of zidovudine:
ZDV converts into Zidovudine triphosphate(active form) in body similar to
thymidine triphosphate(used by HIV to form DNA) hence HIV uses Zidovudine
triphosphate instead of thymidine triphosphate & interferes with the reverse
transcriptase enzyme
Absorption Rapid and nearly complete
Bioavailability 75%
Metabolism Hepa c by glucuronide
conjugation
Elimination Unchanged in urine
Half life 0.5 to 3 hours
Plasma protein binding 30-38%

14. MARKETED PRODUCTS:
ADVERSE EFFECTS:
Abacavir: Musculoskeletal pain (5-7%),Hypertriglyceridemia (6%),Hepa c:
AST Increased (6%),Depression (4-6%),Fever/chills (3-6%),Viral respiratory
infec ons (5%),Ear/nose /throat infec ons (4-5%),Rash (4-5%),Anxiety
(3-5%),Thrombocytopenia (1%)
Zidovudine: Liver damage, pancrea s - severe pain in your upper stomach
spreading to your back, fast heart rate, peripheral neuropathy - numbness,
ngling, or pain in your hands or feet, easy bruising or bleeding, unusual
weakness, pale skin, white patches or sores inside your mouth or on your lips,
fever.

15. materials
RAW MATERIALS CATEGORY MANUFACTURER
Abacavir API Aurobindo pharma ltd.,hyd
Zidovudine API Aurobindo pharma ltd.,hyd
Microcrystalline
cellulose
Diluent,Polymer Signet chemicals,mumbai
Sodium starch glycolate Disintegrant Signet chemicals,mumbai
Talc An adherant Signet chemicals,mumbai
Lactose Diluent Aurolab,Madurai
Magnesium stearate Lubricant SD fine chemicals ltd,mumbai

16. equipments
EQUIPMENTS MODEL MANUFACTURERS
Digital balance AND GP-12K Electro lab
Bulk density apparatus TD 1025 Lab india
16 sta on compression
machine
CM D3-16 Cadmach
Tablet hardness tester PTB-311E Pharmatest
Disintegra on test
apparatus
ED-2L Thermolab
Tablet dissolu on
apparatus(8 bowls)
14000(auto) Lab india
UV- Visible
spectrophotometer
3000+ Lab india

17. methodology
1.Manufacturing
a)formulation planning -selection of API
- diluent,polymer
-disintegrant
-other excepients
b)preparation
2.Drug execipient compatibility studies
3.Determination of λ max
4.Pre formulation studies
a)bulk density
Bulk density = weight of the powder/ bulk volume
b)tapped density
Tapped density = weight of powder / tapped volume.
c)compressibility index
Carr’s index=(Tapped density- Bulk density/Tapped density)*100

18. d)Hausners ratio
Hausner’s ratio=Tapped Density/Bulk Density
e)Angle of repose
5.Post compression studies
a)physical appearance
b)hardness test
c)tablet size and thickness
d)friability
% friability = (initial weight – final weight) / initial weight * 100
e)average weight of tablets
f)disintegration test
g)drug content uniformity
h)dissolution
6.Release kinetics
7.Stability studies
a)long term,intermediate,acclerated
b)forced degradation

19. formulae
INGREDIENTS F1 F2 F3 F4 F5 F6
Abacavir 300 300 300 300 300 300
Zidovudine 300 300 300 300 300 300
Micro crystalline
cellulose
95.25 86.75 91 82.5 99.5 103.75
Lactose 95.25 86.75 91 82.5 99.5 103.75
Sodium starch
glycolate
42.5 59.5 51 68 34 25.5
Magnesium stearate 8.5 8.5 8.5 8.5 8.5 8.5
Talc 8.5 8.5 8.5 8.5 8.5 8.5
Total weight(mg) 850 850 850 850 850 850

20. Results and discussion
ABACAVIR
Conc.(µg / ml) Absorbance (277 nm)
0 0
10 0.0997
20 0.1821
30 0.2861
40 0.3752
50 0.4695

21. ZIDOVUDINE
Conc.(µg / ml) Absorbance (278nm)
0 0
10 0.0999
20 0.2009
30 0.2977
40 0.3949
50 0.4879

22. PRE COMPRESSION PARAMETERS
S. No Formula on
s
Bulk
Density
(gms/ml)
Tapped
Density
(gms/ml)
Angle of
Repose
C.Index Hausner’s
Ra o
1 F1 0.5443 0.6766 25.74 19.5652 1.2432
2 F2 0.5795 0.6710 26.28 13.6363 1.1579
3 F3 0.5669 0.6714 26.06 15.5555 1.1842
4 F4 0.5802 0.6718 27.40 13.6363 1.1579
5 F5 0.5797 0.6712 28.72 13.6363 1.1579
6 F6 0.5668 0.6712 28.65 15.5555 1.1842

23. POST COMPRESSION PARAMETERS
S. No Formula
ons
Weight
Varia on
(mg)
Hardness
(kg/cm2
)
Drug
Content
Uniformity (%)
Friability
(%)
Disintegra
on
Time(min)
1 F1 849.6 4.18 100 0.32 12.50
2 F2 850.3 4.28 99 0.26 10.03
3 F3 850.9 4.35 100 0.25 11.11
4 F4 849.1 4.42 100 0.26 13.55
5 F5 850.5 4.90 99 0.23 12.85
6 F6 849.7 5.00 99 0.26 11.52

24. FTIR GRAPH
ABACAVIR & ZIDOVUDINE

25. IN-VITRO DISSOLUTION
Time
(min)
% Cumula ve Drug release
F1 F2 F3 F4 F5 F6
0 0 0 0 0 0 0
10 21 27 30 33 29 31
20 39 41 44 49 44 46
30 45 55 54 54 52 59
40 48 61 62 64 71 73
50 61 68 85 88 87 89
60 67 72 87 92 94 98

26. COMPARISION OF IN-VITRO DISSOLUTION OF FORMULATIONS F1-F6

27. RELEASE PROFILE OF OPTIMISED FORMULATION (F6)WITH MARKETED
PRODUCT ZIAGEN & RETROVIR

28. RELEASE KINETICS
Formulation Code Zero Order First Order Higuchi’s Peppas’s
F6 0.9370 0.9790 0.9812 0.9720

29. HIGUCHI AND KORSEMEYER PEPPAS PLOT

30. Percentage Cumulative release for stability samples of optimized formulation
(F6) at 400
C / 75% RH and 550
C for 1 & 3 MONTHS
% Cumula ve Drug Release 3 months 3months
Time
(Min)
Initial
550
C
(Forced
Degradatio
n)
1 month
400
C /
75% RH
(Acclerated)
1 month
550
C
(Forced
Degradation
)
400
C / 75%
RH
(Acclerated)
0 0 0 0 0 0
10 31±5.0 30±4.5 30±4.1 30±4.8 29±5.1
20 46±4.9 45±4.1 44±3.5 45±4.1 44±5.2
30 59±4.0 59±3.2 59±2.9 57±3.5 57±2.6
40 73±3.2 72±4.1 71±1.8 72±2.1 71±4.2
50 89±2.1 89±4.0 88±1.1 88±2.0 87±2.9
60 98±2.0 97±2.1 96±1.0 97±1.8 96±1.2

31. Dissolution profiles of 1 & 3 months stability samples at different
conditions initial, 400
C / 75% RH and 550
C

32. Evaluation for stability studies of optimized formulation (F6) after 1
& 3 months stability testing
Parameter Ini al
550
C
1 month
400
C / 75% RH
1 month
550
C
3 months
400
C / 75% RH
3 months
Color White White White White White
Surface Smooth Smooth Smooth Smooth Smooth
Thickness
(mm)
6.40 mm 6.40 mm 6.41 mm 6.42 mm 6.41 mm
Hardness
(kg/cm2
)
4.0-5.0 4.0-5.0 4.0-5.0 4.0-5.0 4.0-5.0
Weight (mg) 850 ± 0.11 850 ± 0.76 850 ± 1.89 850 ± 0.76 850 ± 1.89
Assay 99.12% 98.45% 97.99% 98.90% 97.98%

33. Summary & conclusion
➢For the treatment of Acquired immunodeficiency syndrome (AIDS),
Abacavir and Zidovudine immediate release tablets are formulated. The
Zidovudine added to the formula on to poten ate the synergis c ac vity
of the Abacavir. Which can be beneficial for future development .
➢These current results demonstrated that F6 formula on showing good
characteris cs in pre ,post compression studies, release kine cs even
when compared to their marketed products.
➢A result from stability studies confirms that the developed formula on is
stable and could not show any altera ons.
➢Thus, the present study concludes that medicines must con nually
improve which becomes a building blocks towards novel inven on .

34. references
➢ Vikramjit Singh, Nawazish Alam, Monika Sharma, Md. Sarfaraz Alam, Md. Sajid
Ali, Md. Intakhab Alam. Development, Evalua on and Stability Studies of
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Applied Pharmaceu cal Science 2 (09); 2012: 149-154.
➢ D. Varun, B.V.P. Deepthi, P.V. Ayodhya Neelima, G. Suma Latha, M. Srikar, B.
Anuhya and V. Siva Lalitha. Formula on and In Vitro Assessment of Controlled
Release Matrix Tablets of Abacavir.RJPDFT 2011:3(6); 298-303
➢ Srikanth Thota, A.k.Radhalakshmi, .lamivudine,zidovudine and nevirapine.
Thota et al., IJPSR, 2011; Vol. 2(7): 1772-1776.
➢ Kayitare E, Vervaet C, Ntawukulilyayo J, Seminega B, Bortel V, Remon J.
Development of fixed dose combina on tablets containing zidovudine and
lamivudine for paediatric applica ons. Int J Pharm. 2009; 370:41–46.
➢ Punna Rao Ravi, Udaya Kanth Kotreka, Ranendra Narayan Saha. Controlled
Release Matrix Tablets of Zidovudine: Effect of Formula on Variables on the In
Vitro Drug Release Kine cs. AAPS Pharmscitech March 2008, Volume 9, Issue 1,
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➢ Navarrete MS, Castelo A. Zidovudine (ZDV) and Lamivudine (3TC) Combina on
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