DYNAMIC DISSOLUTION AND STABILITY STUDY OF EFAVIRENZ TABLET TO CHECK THE SUITABILITY OF THE UV METHOD FOR TABLET DISSOLUTION STUDY OF THIS SINGLE COMPONENT FORMULATION

DYNAMIC DISSOLUTION AND STABILITY STUDY OF EFAVIRENZ

TABLET TO CHECK THE SUITABILITY OF THE UV METHOD FOR

TABLET DISSOLUTION STUDY OF THIS SINGLE COMPONENT

FORMULATION.

Ajit.K.Nangare1*, Abhishek.K.Shinde2, Karan.K.Pawa3, Amit N Chavan4

1*

Asst Prof Department of Pharmaceutical Chemistry, Padmashri Dr.Vithalrao Vikhe Patil Foundation’s College of Pharmacy, Vilad Ghat, Ahmednagar, (MS), India, 414111. 2_{Department of Pharmaceutical Chemistry, Padmashri Dr.Vithalrao Vikhe Patil Foundation’s}

College of Pharmacy, Vilad Ghat, Ahmednagar, (MS), India, 414111. 3

Department of Pharmaceutical Chemistry, Padmashri Dr.Vithalrao Vikhe Patil Foundation’s

College of Pharmacy, Vilad Ghat, Ahmednagar, (MS), India, 414111. 4

Padmashri Dr.Vithalrao Vikhe Patil Foundation’s College of Pharmacy, Vilad Ghat,

Ahmednagar, (MS), India, 414111.

ABSTRACT

Efavirenz is one of a new class of anti –viral drugs called

non-nucleoside reverse transcriptase inhibitor (NNRTI). It offers the unique

therapeutic prospect of treatment & management of disease and so

used extensively as a single component formulation. Recently it is

under clinical trials in combination with other anti-viral agents. There

are no official methods reported for estimation of efavirenz. Literature

survey has indicated that there are few spectrophotometric methods for

its estimation in human plasma and urine. Objective of this study is to

check the suitability of the UV method for tablet dissolution study of

this single component formulation and also stability study of efavirenz

in 0.1m HCl is studied in this study. Percentage drug release at 60 min

is maximum as per the cumulative dissolution calculations.

KEYWORDS: Efavirenz, Anti-Viral, Dissolution study, Zero order spectrum method, Stability study.

Volume 4, Issue 5, 1715-1722. Research Article ISSN 2277– 7105

Article Received on 28 Feb 2015,

Revised on 19 March 2015, Accepted on 11 April 2015

*Correspondence for

Author

Ajit. K. Nangare

Asst Prof Department of

Pharmaceutical Chemistry,

Padmashri Dr.Vithalrao Vikhe Patil Foundation’s

College of Pharmacy, Vilad

Ghat, Ahmednagar, (MS),

INTRODUCTION

Efavirenz (EFZ) is a non-nucleoside reverse transcriptase inhibitor (NNRTI). These drugs act by inhibiting HIV’s reverse transcriptase enzyme, but in a different way from the nucleoside

analogue drugs like AZT (zidovudine, Retrovi), abacavir (Ziagen), d4T (stavudinne, Zerif),

3TC (lamivudine, Epivir), ddc (Calcitabine, Hivid) and ddI (didanosine, Videx / VidexEC).

Similar to zidovudine, EFZ inhibits the activity of viral RNA – directed DNA polymerase

(i.e. reverse transcriptase). Antiviral activity of EFZ is dependent on intracellular conversion

to the active triphosphorylated form. The rate of EFZ phosphorylation varies, depending on

cell type. It is believed that inhibition of reverse transcriptase interferes with the generation of

DNA copies of viral RNA, which, in turn, are necessary for synthesis of new virions.

Intracellular enzymes subsequently eliminate the HIV particle that previously had been

uncoated and left unprotected, during entry into the host cell. Thus, reverse transcriptase

inhibitors are visustatic and do not eliminate HIV from the body. Even though human DNA

polymerase is less susceptible to the pharmacologic effect of triphosphorylated Efavirenz, this action may nevertheless account for some of the drug’s toxicity. Chemically efavirenz is

known as 8-chloro

–5-(2-cyclopropylethynyl)-5-(trifluoromethyl)-4-oxa-2-azabicyclo[4.4.0]deca- 7,9,11-trien-3-one.

Efavirenz

Efavirenz was previously determined by Spectrophotometry[1-3], HPTLC [4], HPLC [5-7], and

LCMS.[8] However no such simple, sensitive and précised spectrophotometric method is yet

reported for this drug in any official literature. In our previous study we have developed an

simple, precise, accurate, sensitive, rapid and economic UV Spectrophotometric method of

EFZ in bulk and Pharmaceutical formulations.[9] Objective of this study is to check the

suitability of the UV method for tablet dissolution study of this single component formulation

Introduction to dissolution

Dissolution is the process by which a solid of only fair solubility characteristics enters into

solution. The earliest reference to dissolution is probably in the 1897 by Noyes and Whitney,

"The Rate of Solution of Solid Substances in Their Own Solution". The authors suggested

that the rate of dissolution of solid substances is determined by rate of diffusion of a very thin

layer of saturated solution that forms instantaneously around a solid particle. They developed

a mathematical relationship that correlates the dissolution rate to solubility gradient of the

solid. Their equation is still the basic formula upon which most of modern mathematical

treatments of dissolution phenomenon revolves. To examine their data quantitatively, Noyes

and Whitney developed an equation based on Pick's second law, to describe the dissolution

phenomenon.

Figure 1: Diffusion layer model (film theory)

The Noyes and Whitney equation states that

dc /dt =K (Cs-Q)

Where,

dc/dt = The Dissolution rate of the drug.

K. = Proportionality Constant (also called the dissolution constant).

Cs = Saturation concentration (maximum solubility).

Ct = Concentration at time t.

Cs - Ct) = Concentration gradient.

Sink Condition

A mechanism exists by which the dissolution medium is replenished constantly with fresh

solvent at a specified rate so that the concentration of solute never reaches more than 10% to

said to be conducted under sink condition, meaning under no influence of the concentration

gradient.

,

Figure 2 represents plots of data that would be expected under sink and non sink condition

Figure 2

(a) Linear (dissolution rate under non sink condition)

(b) Semi-log first order kinetic plot of (dissolution rate under non sink condition)

(c) Linear zero-order kinetic plot (dissolution rate under sink condition)

Factor related to the physicochemical properties of the drug

The important factors correlating the dissolution rate with the physicochemical properties of

the drug include.

 Effect of solubility on dissolution

The physicochemical properties of the drug substances play a prime role in controlling its

dissolution from the dosage form. According to Noyes and Whitney, the aqueous solubility of

the drug is the major factor that determines its dissolution rate. Actually some studies showed

that drug solubility data could be used as a rough predictor of the possibility of any future

problems with bioavailability, a factor that should be taken into consideration in the

formulation design.

 Effect of particle size on dissolution:

According to Noyes and Whitney, a direct relationship exists between the surface area of the

drug and its dissolution rate. Because the surface area increases with decrease in particle size,

has been highlighted by the superior dissolution rate observed after micronization of a certain

sparingly soluble drugs as opposed to the regularly milled form. Micronization increases the

surface area exposed to the dissolution medium and hence improves the rate of dissolution.

 Effect of the crystalline state of the drugs on dissolution

The solid phase characteristics of drugs - such as amorphicity, crystallinity, state-of hydration

and polymorphic structure have been shown to have a significant influence on the dissolution

rate.

MATERIALS AND METHODS

Instrumentation specifications of dissolution test systems.

Make and model: VEEGO, VDA-6D

Number of Test Stations: Six (6) Nos.

Number of Vessels: 7 Nos.

Stirrer Speed Range: 25 to 200 RPM.

Vessel Capacity: One (1) Litre

Temperature Range: 3°C above Ambient Temperature to 40°C, Adjustable to 0.1° C.

Stirrer Speed Accuracy: Better than ± 1 RPM.

Timer Range: 1 minute to 24 hours.

Power Supply: 230 Volts, 50 Hz.

Power Consumption: 1300 VA (Max.).

The commercially available tablets, Sustiva (Label claim: Efavirenz- 600mg) was procured

from local Market.

Dissolution study of EFZ from tablet by Zero Order spectrum method:

Release kinetics of EFZ from tablets was studied by conducting dissolution tests. Dissolution

test were perform using USP type II dissolution apparatus & 900 ml 0.1 N HCl. As tablet is

of conventional formulation, time selected for dissolution was 2 hour. Quantity of dissolution

medium was taken such that maximum release of drug should be 100% in pipetted sample.

With 0.1 N HCl results were satisfactory. Temperature of dissolution media was set at 37 

0.5oC with paddle revolving at 100 rpm. 10 ml of sample solution was withdrawn at interval

of 10 min & from that 10ml sample, withdrawn 1ml of sample & dilute it with methanol &

makeup the volume upto 10 ml for whole of dissolution study of 2 hour. To maintain sink

same temperature (37  0.5 oC). Withdrawn 10 ml sample solution contain of EFZ at 100%

resulting solution were analyze by zero order spectrum method of UV-Visible

spectrophotometry. Dissolution studies perform in triplicates. Percentage drug release at 60

min is maximum as per the cumulative dissolution calculations.

Table 1: % Release of EFZ from tablet Sustiva in 0.1 N HCL Time (Min) % of Drug released for Nelvir

10 82.10%

20 82.18%

30 90.56%

40 92.39%

50 93.26%

60 97.10%

70 95.39%

80 93.69%

90 91.32%

100 91.74%

110 88.91%

120 87.74%

*Average of three readings.

Figure 3: % Release of EFZ from tablet formulation in 0.1 N HCl

Stability study of EFZ tablet

Stability study of efavirenz tablet was done by checking its absorbance in uv zero order

Table 2: Stability study of EFZ

Figure 4: Zero order spectrum of EFZ tablet in 0.1N HCl

RESULTS AND DISSCUSSION

Withdrawn 10 ml sample solution contain of EFZ at 100% resulting solution were analyze by

zero order spectrum method of UV-Visible spectrophotometry. Dissolution studies perform

in triplicates. Percentage drug release at 60 min is maximum as per the cumulative

dissolution calculations. Stability study indicate that according to uv zero order spectrum the

absorbance of EFZ tablet is constant from 0 to 60 min, recorded at each 5 min interval and

also the zero order spectrum graph shown in figure 4 is proof for stability of EFZ tablet.

CONCLUSION

According to the dissolution study performed and depending upon the zero order spectra of

EFZ the drug can be estimated by simple, easy and precise uv spectroscopy method and the

dissolution study of EFZ tablet can be performed by this method and it is concluded that this

Sr. No. Time (Min) Absorbance

1 0 0.733

2 5 0.733

3 10 0.734

4 15 0.734

5 20 0.735

6 25 0.735

7 30 0.735

8 35 0.736

9 40 0.734

10 45 0.735

5 50 0.734

12 55 0.734

method can be used by the industries and academic institutions for their drug estimation,

which is rapid as well as novel.

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