Formulation and Evaluation of Efavirenz 600 mg Tablet

Mohd. Yaqub Khan^2*, Maryada Roy¹, Imtiyaz Ahmad², Irfan Aziz², Manju Panday²

¹Mangalayatan University, Beswan, Aligarh, Uttar Pradesh, India

²Azad Institute of Pharmacy and Research Azadpur, Adjacent CRPF Camp, Bijnour,

Lucknow - 226 002, Uttar Pradesh, India

*Corresponding Author E-mail: khanishaan16@yahoo.com

ABSTRACT:

Aim: Formulation and Evaluation of Efavirenz 600 mg Tablet.

Methodology: Accurately weighed amount of selected additive concentrates (F1, F2, F3, F4, F5, F6) representing 600 mg equivalent of drug was mixed with directly compressible excipients i.e. Croscarmellose Sodium and Sodium Starch Glycolate as superdisintegrants, Talcum as diluents and microcrystalline cellulose as diluents. Obtained mixture was subjected for wet granulation. Water was added and mixed thoroughly to form dough mass. The mass was passed through mesh no. 12 to obtain wet granulation. The wet granules were dried at 60° C for 4 hours. Dried granules were passed through mesh no. 16 to break aggregates. Lubricants talcum and magnesium stearates were passed through mesh no. 100 on to dry granules and blended in a closed polyethylene bag. The tablet granules were compressed by using 16 station tablet compression machine (electrical Motor-Crompton Greaves and A.C. Drives-Siemens) to a hardness of 5-6 kg/cm2 using 9 mm flat punches. In each case 500 tablets were compressed. Prepared tablets were collected in a poly bag.

Results: Evaluation of developed formulation for various pre-compression and post-compression parameters was found to be within pharmacopoeial limits.

Pre-compression parameters of the formulation- Pre-compression parameters were characterized on the basis of their physical parameters. Bulk density (0.338 g/ml), Tapped density (0.458 g/ml), Compressibility ratio (23.89 %), Hausner’s ratio (1.38).

Post-compression parameters: Weight variation, hardness and friability pass U.S.P. specification. Tablets of all formulation showed good physical appearance, disintegration test indicated that the tablets of all formulation were dissolved in desire time. Disintegration time of all the formulation have to be less than 45 minute. Disintegration time of the various formulation were found in following order in min F5 (8.10±0.39)>F6 (8.15±0.42)>F3 (8.33±0.43)> F2 (8.35±0.46)> F4 (8.37±0.47)> F1 (8.40±0.43).

This is due to F5 and F6 contain maximum concentration of superdisintegrants (CCS-8.5%, SSG-9.2%), than followed by other formulation. Weight variation tests, hardness and friability test indicated that, tablets of all formulation were having good compactness and mechanical strength and passes U.S.P. specification.

In-vitro dissolution studies revealed that the release rate of Efavirenz coated tablets were found to be in following order F6>F5>F4>F3>F2>F1. This is due to F6 contain maximum concentration of superdisintegrants concentration.

KEYWORDS: Efavirenz, Superdisintegrants, Weight variation.

1. INTRODUCTION:

In the last 25 to 30 years, a huge resource in both academia and industry has been devoted to the development of drug delivery systems that target drugs more effectively to their therapeutic site. Much of this work has been successful, and is reported in this text. In spite of this, oral solid dosage forms such as tablets, which have been in existence since the 19^th century, remain the most frequently used dosage forms. This is not simply a reflection of the continued use of established products on the market, tablets and capsules still account for about half of all new medicines licensed¹.

Tablet is a major category of solid dosage forms which are widely used worldwide. Extensive information is required to prepare tablets with good quality at high standards. Based on preformulation studies, the optimal dosage forms are generally decided. When give orally, the solid dosage form tablet undergoes In vitro disintegration and dissolution followed by absorption through gastrointestinal (GI). The In vivo bio-distribution of drug which enters the systemic circulation then occurs.

Salient Features of Tablets²

· Tablets are convenient to use and are an elegant dosage form.

· A wide range of tablets types is available, offering a range of drug-release rates and durations of clinical effect. Tablets may be formulated to offer rapid drug release or controlled drug release, the latter reducing the number of daily doses required (and in so doing increasing patient compliance).

· Tablets may be formulated to release the therapeutic agent at a particular site within the gastrointestinal tract to reduce side effects, promote absorption at that site and provide a local effect (e.g. ulcerative colitis). This may not be easily achieved by other dosage forms that are administered orally.

· Tablets may be formulated to contain more than one therapeutic agent (even if there is a physical or chemical incompatibility between each active agent). Moreover, the release of each therapeutic agent may be effectively controlled by the tablet formulation and design.

· With the exception of proteins, all classes of therapeutic agents may be administered orally in the form of tablets.

· It is easier to mask the taste of bitter drugs using tablets than for other dosage forms, e.g. liquids.

· Tablets are generally an inexpensive dosage forms.

· Tablets may be easily manufactured to show product identification, e.g. exhibiting the required markings on the surface.

· The chemical, physical and microbiological stability of tablet dosage forms is superior to other dosage forms.

Challenges in Formulating Tablet³

· The manufacture of tablets requires a series of unit operations and therefore there is an increased level of product loss at each stage in the manufacturing process.

· The absorption of therapeutic agents from tablets is dependent on physiological factors, e.g. gastric emptying rate, and show inter patient variation.

· The compression properties of certain therapeutic agents are poor and may present problems in their subsequent formulation and manufacture as tablets.

· The administration of tablets to certain groups, e.g. children and the elderly may be problematic due to difficulties in swallowing. These problems may be overcome by using effervescent tablet dosage forms.

Human Immunodeficiency Virus Infection/ Acquired Immunodeficiency Syndrome (HIV/AIDS)

In 2004, an estimated 42 million people were living with HIV infection worldwide, mostly in resource-poor countries. Of these who would benefit, fewer than 5% were receiving combination antiretroviral therapy, even though such treatment reduces the complications of infection and has the capacity to produce near normal life expectancies for some patients with a previously lethal disease⁴.

Human Immunodeficiency Virus Infection/ Acquired Immunodeficiency Syndrome (HIV/AIDS) is a disease of the human immune system caused by infection with human immunodeficiency virus (HIV). During the initial infection, a person may experience a brief period of influenza-like illness. This is typically followed by a prolonged period without symptoms. As the illness progresses, it interferes more and more with the immune system, making the person much more likely to get infections, including opportunistic infections and tumors that do not usually affect people who have working immune systems.

HIV is a member of the genus Lentivirus, part of family Retroviridae. Lentiviruses have many morphologies and biological properties in common. Many species are infected by lentiviruses, which are characteristically responsible for long-duration illnesses with a long incubation period. Lentiviruses are transmitted as single-stranded, positive-sense, enveloped RNA viruses⁵.

Types of HIV/AIDS

One of the obstacles to treatment of the Human Immunodeficiency virus is its high genetic variability. HIV can be divided into two major types, HIV type 1 (HIV-1) and HIV type 2 (HIV-2)^{6, 7}.

1. HIV-1

HIV-1 is the most and pathogenic strain of the virus. Scientists divide HIV-1 into a major group (Group M) and two or more minor groups. Each group is believed to represent an independent transmission of SIV into humans (but subtypes within a group are not). Total 39 ORFs are found in all six possible reading frames (RFs) of HIV-1 complete genome sequence. But only few of them are functional.

2. HIV-2

HIV-2 has not been widely seen outside of Africa. The first case in the United States was in 1987. Many test kits for HIV-1 will also detect HIV-2. AS of 2010, there are 8 known HIV-2 groups (A to H). Of these, only groups A and B are epidemic. Group A spread mainly in West Africa, but also to Angola, Mozambique, Brazil, India, and very limited to Europe or the US. Group B is mainly confined to West Africa.

HIV-2 is mostly related to simian immunodeficiency virus endemic in sooty mangabeys (Cercocebus atys atys) (SIV smm), a monkey species inhabiting the forests of littoral West Africa. Phylogenetic analysis show that the viruses most closely related to the two strains of HIV-2 which spread considerably in humans (HIV-2 groups A and B) are the SIV smm found in the sooty mangabeys of the Tai forest, in Western Ivory Coast.

There are six additional known HIV-2 groups, each having found in just one person. They all seem to derive from independent transmission from sooty mangabeys to humans. Group C and D have been found in two people from Liberia, Groups E and F have been discovered in two people from Sierra L, and Groups G and H have been detected in two people from the Ivory Coast. Each of these HIV-2 strains, for which humans are probably dead-end hosts, is most closely related to SIV smm strains from sooty mangabeys living in the same country where the human infection was found⁸.

Drugs Used in HIV/AIDS⁹

(1) Nucleoside and Nucleotide Reverse Transcriptase Inhibitors

Zidovudine, Lamivudine, Stavudine, Didanosine, Abacavir, Zalcitabine, Tenofovir, Emtricitabine

(2) Non-Nucleoside Reverse Transcriptase Inhibitors

Nevirapine, Efavirenz, Delavirdine

(3) HIV Protease Inhibitors

Aquinavir, Ritonavir, Indinavir, Nelfinavir, Fosamprenavir, Lopinavir, Atazanavir, Tipranavir

(4) Entry Inhibitors

Enfuvirtide

(5) CCR-5 Receptor Inhibitor

Maraviroc

(6) Integrase Inhibitor

Raltegravir

2. METHODOLOGY:

2.1 MATERIAL AND METHOD:

The following materials and equipment were used for the development of the formulation as shown in table 1.1

Table 1.1: List of Material Used in the Tablet Formulation:

S. No.	Materials	Category	Manufactures/Suppliers
1	Efavirenz	API	Aurobindo Phrama LTD. Gaddapotharam Jinnaram, Andhra Pradesh
2	Microcrystalline Cellulose	Diluent	International Speciality Product Technologies Limited, USA
3	Croscarmellose Sodium	Superdisintegrants	International Speciality Product Technologies Limited, USA
4	Polyvinylpyrrolidone (PVP) K-30	Binder	International Speciality Product Technologies Limited, USA
5	Sodium Starch Glycolate	Superdisintegrants	International Speciality Product Technologies Limited, USA
6	Lactose	Diluent	S.D. Fine Chemicals Limited, Mumbai, India
7	Talcum	Lubricant and Diluent	S.D. Fine Chemicals Limited, Mumbai, India
8	Magnesium stearate	Lubricant	Qualigens Fine Chemicals, Mumbai, India
9	Isopropyl alcohol	Solvent	Qualigens Fine Chemicals, Mumbai, India
10	Sodium lauryl sulphate	Anionic Surfactant	Qualigens Fine Chemicals, Mumbai, India

Table 1.2: List of Material Used in Tablet Coating:

S. No.	Materials	Category	Manufactures/ Suppliers
1	Hydroxypropyl methylcellulose (HPMC)	Adhesives	International Speciality Product Technologies Limited, USA
2	Polyethylene glycols 6000	Biodegradable Polymeric Matrices	International Speciality Product Technologies Limited, USA
3	Isopropyl alcohol (IPA)	Solvent	International Speciality Product Technologies Limited, USA
4	Methyl dichloride	Solvent	S.D. Fine Chemicals Limited, Mumbai, India
5	Titanium dioxide	White pigment and Opacifier	Qualigens Fine Chemicals, Mumbai, India
6	Talcum	Lubricant and Diluent (preventing sticking)	S.D. Fine Chemicals Limited, Mumbai, India
7	Red oxide iron	Colorants	Qualigens Fine Chemicals, Mumbai, India

Table 1.3: List of Equipments Used in the Tablet Formulation Development:

S. No.	Equipments	Manufactures/Suppliers
1	Ultra violet-visible spectrophotometer Model-T-70	Pharmaspec 1700 SHIMADZU, Japan
2	Fourier Transform Infrared Spectrophotometer	Jasco FT-761, Japan
3	Differential Scanning Calorimeter	Perkin Elmer Pyris6 DSC
4	Scanning Electron Microscope	Zeiss EVO® 50, U.K.
5	16 Station Tablet Compression Machine	Electrical Motor-Crompton Greaves and A.C. Drives-Siemens.
6	Dissolution Test Apparatus USP Std. Model-VDA-6 DR	HICON®, Grover Enterprises, New Delhi, India
7	Magnetic Stirrer with Hot Plate	Jindal, S.M. Scientific Instruments (P) Ltd., Delhi, India
8	IR-Moisture Balance Apparatus Model-RSMH-2-S	Sartorious-Ma45 Stedim India Pvt. Ltd., Bengaluru
9	Melting Point Apparatus	Jindal, S.M. Scientific Instruments (P) Ltd., Delhi, India
10	High Accuracy Single Pan Balance	Sansui Electronics JW, Parwanoo (H.P.), India
11	Hardness Tester Model-VHT-1	HICON®, Grover Enterprises, New Delhi, India
12	Tap Density Apparatus Model-VTAP/MATIC-II	HICON®, Grover Enterprises, New Delhi, India
13	pH/ milivoltmeter	HICON®, Grover Enterprises, New Delhi, India
14	Roche Friabilator USP Model-VFT-2D	Electrolab Ltd., Goregaon, Mumbai, India
15	Tray Dryer	Jindal, S.M. Scientific Instruments (P) Ltd., Delhi, India
16	Verniercaliper	Mitotoyu Pvt. Ltd., South East Asia
17	Standard Test Sieves (100 mesh)	HICON®, Grover Enterprises, New Delhi, India
18	Disintegration Apparatus Model-VTD-D	HICON®, Grover Enterprises, New Delhi, India
19	Automatic Sieve Shaker	Cambridge Environment Products Inc., Canada
20	Comminuting Mill	Shiv Pharma Engineers, Ahmedabad, Gujarat, India
21	Multi mill Machine Size Reduction	Jindal, S.M. Scientific Instruments (P) Ltd., Delhi, India
22	Sifter	Shiv Pharma Engineers, Ahmedabad, Gujarat, India
23	Tablet Coating Machine	Jindal, S.M. Scientific Instruments (P) Ltd., Delhi, India

2.2 Preformulation Study

Preformulation is the first step in the rational development of doses form of a drug substance and it is defined as an investigation of physicochemical properties of a drug substance and alone or when combined with excipients. The goal of preformulation is to investigate critical physicochemical factors which assure identity and purity of drugs substance, product preformulation or quality¹⁰.

2.2.1 Identification Test Listed in the Monograph¹¹

· Melting Point Determination: Melting Point of drug was determined by capillary fusion method using melting point apparatus. The melting point obtained was recorded and compared with the literature value (European Pharmacopoeia).

· UV Spectrophotometric Studies: Efavirenz (10 mg) was accurately weighed and transferred to a 100 ml volumetric flask. It was dissolved and diluted to 100 ml with methanol of 10µg/ml. Dilutions were made to obtain a concentration of 10µg/ml and scanned for ƛ max was recorded and compared with literature value (European Pharmacopoeia).

· Differential Scanning Calorimetry (DSC): DSC has also been used to monitor the kinetics and thermodynamics of decomposition processes for drug substance alone and in the presence of excipients. Various software packages are available to quantitatively evaluate kinetic studies performed using thermal analysis and to calculate the activation energy, pre-exponential factor, and rate constant from either dynamic or isothermal experiments.

DSC has been used to some extent in early scanning studies to evaluate drug-excipient compatibility, with the goal of obtaining rapid results with minimal drug substance. Binary mixtures of drug-excipient are typically subjected to a programmed temperature ramp, and the resultant thermo grams are compared to the thermo grams of the individual components. If there are no interactions, one should observe a thermo gram that is a combination of the contribution of the thermal transitions observed alone for each drug and excipient. However, if interactions do occur, new thermal events are observed that deviate from the original thermo grams.

2.2.3 Calibration

Ongoing calibration will help to assure that the chamber is working properly over time. Calibration can be performed by placing a temperature and/or relative humidity standard inside the chamber (near the probe used by the chamber controller).

After the chamber has re-equilibrated, record the standard readings and the controller readings. The temperature and relative humidity readings should agree to within a certain range. This range should be set by the firm in the calibration SOP and it should be based on the accuracy of the test equipment being used. I have seen a temperature specification set at ±1 °C and a relative humidity specification set at ±3% RH, when calibration is performed using a Vaisala hand-held monitor, Model HMI41 (with HMP45 probe). This probe is accurate to within ±0.6 °C and ±2% RH. Other wired or wireless monitors with comparable accuracy may be acceptable.

2.2.4 Determination of Bulk Density

The volume of powder packing was determined on an apparatus consisting of a granulated cylinder mounted tapping device that has a specially cut rotating cam. An accurately weighed 50 g of powder was carefully added to the cylinder with the aid of a funnel. Initial volume of powder was noted and the sample subjected to 750 tapping until no further reduction in volume was noted or the percentage of difference in volume was not more than 2%. A sufficient number of taps were employed to assure reproducibility for the material in equation. The Tapping did not produce particle attrition or a chance in the particle size distribution of the material being tested¹².

Equation number (1.1)

Bulk Density (poured) = Weight of powder/Bulk volume of powder

2.2.5 Tapped Density

Tapped density was determined by poured mass of complex and excipients into 250 ml graduated measuring cylinder and graduated cylinder was then subjected to 100 tapping, using tapped density apparatus, until the change in the volume approached constant value. The method was repeated three times and the mean of the values exhibited as final volume was calculated as a result of tapped volume. Tapped density of the powder was determined by applying the following formula:

Equation number (1.2)

Tapped Density (Tapped) = Weight of powder/ Tapped volume of powder

2.2.6 Compressibility Index

The simplest way of measurement of free flow property of powder is compressibility, an indication of ease with which material can be induced to flow given by % compressibility index (% CI) which was calculated as follows:

Equation number (1.3)

%CI= {(Tapped density-Bulk density)/Tapped density}*100

Table 1.4 Grading of the powders on their flow properties according to Carr’s Index:

Consolidation Index (Carr’s %)	Flow	Hausner’s Ratio
≤10	Excellent	1.00-1.11
11-15	Good	1.12-1.18
16-20	Fair	1.19-1.25
21-25	Passable	1.26-1.34
26-31	Poor	1.35-1.45
32-37	Very Poor	1.46-1.59
>38	Very, very poor	>1.6

2.2.7 Hausner’s Ratio

Hausner’s ratio is an index of ease of powder flow; it is related to interparticulate friction as such, could be used to predict powder flow properties. It is calculated by following formula:

Equation number (1.4)

Hausner’s Ratio= Tapped Density/ Bulk Density

2.2.8 Determination of Angle of Repose

Angle of repose is defined as the maximum angle possible between the surfaces of a pile of powder and horizontal plane. This was determined by passing required quantities of drug granules through a funnel from a particular height (2 cm) onto a flat surface until it formed a heap, which touched the tip of the funnel. The height and radius of the heap were measured. The angle of repose was determined by using the formula¹³.

Equation number (1.5)

Tan ɵ= h/r

Equation number (1.6)

ɵ=tan^-1 (h/r)

Where

ɵ= angle of repose

h=height of pile

r=radius of the base of pile

Different ranges of flow ability in terms of angle of repose are given below in Table 1.5

Table 1.5 Relationship between angle of repose, ɵ and flow properties: ¹⁴

Angle of repose, ɵ (Degrees)	Flow
25-30	Excellent
31-35	Good
36-40	Fair
41-45	Passable
46-55	Poor
56-65	Very poor
>66	Very, very poor

2.2.9 Drug Excipient Compatibility Study

The primary objective of this investigation was to identify the interaction between drug and polymer. Interaction study was carried out according to the following procedure. Drug and excipient were mixed separately placed in glass vials. The vials were sealed and placed in the stability chamber at 25 ± 2°C/ 60±5% RH, 40±2°C/75±5% RH and 55±2°C for 21 days. The sample was analyzed for colour change, and bad odour after 7, 15, and 21 days. The U.V. spectra was taken after 5 and 10 days and analyzed for any shift in absorption maxima.

2.3 Tablet Manufacturing By Wet Granulation

Most product formulators see wet granulation as a universally applicable means of tablet processing. All of the required functionality of a compression mix- good flow, good compatibility, uniform distribution of drug and controllable drug release-can is built in using wet granulation without relying on the intrinsic properties of the drug or the excipient. Additionally using wet granulation it is possible to get stabilizing agents such as pH modifiers into close contact with the drug and so potentially maximize tablet stability.

Figure 1.1: Schematic of Wet Granulation by Low Shear and High Shear Processing

For high dose drugs, poor flow and compaction of the active mean that wet granulation may be only feasible means of producing tablets, and for low dose drugs the granulation process is seen as being capable of “locking” drug into granules and thereby minimizing the potential for segregation and poor content uniformity. There are therefore a number of advantages inherent to wet granulation. Thus despite the board applicability of wet granulation it may be simpler and ultimately more production efficient to first look at direct compression or dry granulation.

Accurately weighed amount of selected additive concentration (F₁, F₂, F₃, F₄, F₅, and F6) representing 200mg equivalent of drug was mixed with direct compressible excipients i.e. Croscarmellose Sodium and Sodium starch glycolate as superdisintegrants, Talcum as diluents and microcrystalline cellulose as diluents. Obtained mixture was subjected for wet granulation and compressed by using 16 station tablet compression machine (electrical Motor-Crompton Greaves and A.C. Drives-Siemens). Prepared tablets were collected in a poly bag¹⁵.

High shear

2.4 Evaluation Parameter of Formulation

2.4.1 Description: Twenty tablets were randomly selected from each formulation and examined for the shape.

2.4.2 Thickness: The thickness of the tablet was measured by using venire calliper, twenty tablets from each batch were randomly selected and thickness was measured.

2.4.3 Weight variation: Twenty tablets were randomly selected from each formulation and weight individually and then average weight of the tablets was calculated and difference of individual weight from the average weight was calculated. The following permissible percentage deviation in weight variation is given in table 1.6.

Table 1.6: USP Specification for Tablet Weight Variation: ¹⁶

Average weight of tablet	Percentage weight variation (%)
130 mg or less	10
More than 130 mg and less than 324 mg	7.5
324 mg or more	5

2.4.4 Hardness:

Six tablets from each batch were taken at random and hardness of the prepared tablets was tested by hardness tester Model-VHT-1 (HICON^®, Grover Enterprises, and New Delhi, India). The mean of 6 determinations was calculated and the value obtained was recorded and reported as hardness in kg/cm².

2.4.5 Friability:

Friability of prepared fast disintegrating tablets was determined by using Roche’s Friabilator ( Electrolab Ltd., Goregaon, Mumbai). 10 tablets from each batch were selected at random and weighted accurately. Tablets were then placed in a plastic chamber that rotates at 25 rpm dropping tablets from a distance of six inches with each revolution. The friabilator was then operated for 100 revolutions after that tablets were dusted and reweighted (British Pharmacopeia, 1998). Friability can be calculated using following equation:

Equation number (1.7)

% Friability= {(Initial weight-Final weight)/Initial weight}*100

2.4.6 Drug Content Uniformity:

Six tablets were crushed and powdered equivalent to 10 mg of drug taken and extracted with 100 ml quantity of methanol. The solution was suitability diluted and the drug content was analyzed spectrophotometrically at wavelength of 252 nm. Each sample was analyzed in triplicate.

2.4.7 Disintegration Time:

The disintegration time of the prepared rapidly disintegrating tablets were determined by using USP disintegrating apparatus containing 900 ml of double distilled water (pH 5.8), maintained at 37°C±0.5°C. Time was recorded when all the fragments of disintegrated tablet passed through the screen of the basket. A mean of three determinations was recorded and reported in seconds, as in-vitro disintegration time.

2.4.8 In-Vitro Drug Release:

Following procedure was employed throughout the study to determine the In-vitro dissolution rate of all the formulations. The dissolution parameters are shown in table 1.7.

Table 1.7: Dissolution Parameters: ¹⁷

Dissolution medium	1% w/v solution of Sodium Lauryl Sulphate
Dissolution medium volume	900 ml
Apparatus	USP-8 Station (Paddle)
Speed	50 rpm
Temperature	37°C±0.5°C
Sampling time	0, 5, 10, 15, 20, 25, 30, 45 min

3. RESULT:

3.1 Preformulation study of Efavirenz:

The present investigation was carried out to develop tablet dosage form of efavirenz. The tablets were prepared using different excipients by wet granulation method.

3.1.1 Efavirenz Characterization Study:

3.1.1.1 Physical Properties:

The drug was found to be off-white, crystalline powder.

3.1.1.2 Solubility Study:

The drug was found to be soluble in methanol, acetone and SLS solution. Solubility of Efavirenz was found to be more in methanol. Therefore methanol was used as dissolution medium. In water it solubilised only 0.03%.

3.1.1.3 Melting Point Determination:

The melting point of the Efavirenz was found to be in the range of 138-140 °C which comply the literature value of 139-141 °C (B.P. 2009), and proved the identity and purity of drug.

3.1.1.4 UV Spectrophotometric Study:

UV Spectrophotometric study of Efavirenz was determined in methanol. Different solutions of Efavirenz (10 µg/ml) was prepared as test mediums and scanned for absorption maxima in the range of 200-300 nm using double beam UV spectrophotometer and result was found to be near about literature value as shown in Table 4.1 and proved the identity and purity of drug.

Table 1.8 Drug Related Identification Tests:

S.No.	Parameters	Experimental Values	Literature Value
1	Melting point	138-140°C	139-141°C (B.P. 2009)
2	UV Spectrophotometric Studies in Methanol	246 nm	252 nm (I.P. 2007)

3.1.2 Powder Flow Properties

3.1.2.1 Angle of Repose:

The angle of repose was determined by measuring the height of the cone of powder and radius of the circular base of powder heap and the observed value at 35.76°, so it was calculated that the flow property was fair.

3.1.2.2 Density Analysis:

The bulk density was found to 0.25 g/ml and tapped density was found to be 0.33 g/ml.

3.1.2.3 Compressibility Index and Hausner’s Ratio:

The compressibility index was 26.21 % and Hausner’s ratio was 1.35%, so it was concluded that the flowability of Efavirenz powder is fair.

Table 1.9 Compositions of Efavirenz Tablets

Ingredients	F1 (mg)	F2 (mg)	F3 (mg)	F4 (mg)	F5 (mg)	F6 (mg)
Efavirenz	200	200	200	200	200	200
Microcrystalline cellulose (MCCP)	66	70	69	69	69	66
Croscarmellose Sodium	18	19	19	20	20	21
Polyvinylpyrrolidone (PVP) K-30	10	9	9	8	7	3
Sodium Starch Glycolate	16	16	17	17	18	16
Lactose	87	80	80	80	80	88
Isopropyl alcohol	-	-	-	-	-	-
Talcum	5	5	5	5	5	5
Sodium Lauryl Sulphate	5	8	8	8	8	8
Magnesium Stearate	3	3	3	3	3	3
Total Weight	410	410	410	410	410	410

3.2 Evaluation Parameters

This was carried out as follows

· Pre-compression parameters

· Post compression parameters

This study included loss on dried granules and final blend, bulk density, tapped density, Carr’s index, Hausner’s ratio and sieve analysis as per compression parameters and average weight, thickness, hardness, disintegration time and friability as post compression parameters.

3.2.1 Pre-compression parameters

3.2.1.1 Angle of Repose: Angle of repose of all the formulation was performed by fixed funnel method and angle of repose was found to be 34° to 36°.

Table 2.0: Angle of Repose of the Formulation

Formulation	F1	F2	F3	F4	F5	F6
Angle of Repose	34.55	35.77	35.45	35.67	34.19	34.12
Flow	Fair	Fair	Fair	Fair	Fair	Fair

3.2.1.2 Bulk Density: Bulk density of all the formulation was found to be in range of 0.333g/ml to 0.337g/ml.

3.2.1.3 Tapped Density: Tapped density of all formulation was found to in the range of 0.454g/ml to 0.459g/ml.

3.2.1.4 Compressibility Ratio and Hausner’s Ratio: Compressibility ratio and Hausner’s ratio of all the formulation was found to be in range of 24.15% to 24.37% and 1.35 to 1.38 respectively. It was concluded that the flow property of all the formulation was fair.

Table 2.1: Pre-Compression Parameters of the Formulations

Formulations	Bulk Density (gm/ml)	Tapped Density (gm/ml)	Carr’s Index (%)	Hausner’s Ratio
F1	0.333	0.454	24.15	1.38
F2	0.334	0.455	24.33	1.34
F3	0.337	0.457	24.27	1.37
F4	0.335	0.456	24.36	1.35
F5	0.334	0.459	24.36	1.37
F6	0.337	0.459	24.37	1.35

3.2.1.5 Excipient Compatibility study via ICH Guide Lines

Excipients are included in dosage forms to aid manufacture, administration or absorption. Other reasons for inclusion concern product differentiation, appearance enhancement or retention of quality.

They rarely, if ever, posses pharmacological activity and are accordingly loosely categorized as “inert”. However, excipients can initiate, propagate or participate in chemical or physical interaction with an active, possible leading to compromised quality or performance of the medication. Chemical interaction can lead to degradation of the active ingredient; thereby reducing products may compromise safety or tolerance. Physical interactions can affect rate of dissolution, uniformity of dose or ease of administration.

Table 2.2: Excipient Compatibility Study with Efavirenz at 40±2°C/75±5% RH

S.No.	Contents	Day				Wet (with 5% moisture)
		Initial	Day 7	Day 15	Day 21	Initial	Day 7	Day 15	Day 21
Vail 1	Efavirenz	White to Off white powder	NC	NC	NC	White to Off white powder	NC	NC	NC
Vail 2	Efavirenz + CCS	White to Off white powder	NC	NC	NC	White to Off white powder	NC	NC	NC
Vail 3	Efavirenz + SSG	Off white powder	NC	NC	NC	Off white powder	NC	NC	NC
Vail 4	Efavirenz + MCC	Off white powder	NC	NC	NC	Off white powder	NC	NC	NC
Vail 5	Efavirenz + PVP K-30	Off white powder	NC	NC	NC	Off white powder	NC	NC	NC
Vail 6	Efavirenz + Lactose	White to Off white powder	NC	NC	NC	White to Off white powder	NC	NC	NC
Vail 7	Efavirenz + Talcum	White to Off white powder	NC	NC	NC	White to Off white powder	NC	NC	NC
Vail 8	Efavirenz + Magnesium Sterates	Off white powder	NC	NC	NC	Off white powder	NC	NC	NC
Vail 9	Efavirenz + SLS	Off white powder	NC	NC	NC	Off white powder	NC	NC	NC

NC=No Change, CCS= Croscarmellose Sodium, SSG= Sodium Starch Glycolate, MCC= Microcrystalline Cellulose, PVP K-30= Polyvinylpyrrolidone, SLS= Sodium Lauryl Sulphate

.

Table 2.3: Exicipient Compatibility Study with Efavirenz at 25±2°C/60±5% RH

S.No.	Contents	Dry				Wet (with 5% moisture)
		Initial	Day 7	Day 15	Day 21	Initial	Day 7	Day 15	Day 21
Vail 1	Efavirenz	White to Off white powder	NC	NC	NC	White to Off white powder	NC	NC	NC
Vail 2	Efavirenz + CCS	White to Off white powder	NC	NC	NC	White to Off white powder	NC	NC	NC
Vail 3	Efavirenz + SSG	Off white powder	NC	NC	NC	Off white powder	NC	NC	NC
Vail 4	Efavirenz + MCC	Off white powder	NC	NC	NC	Off white powder	NC	NC	NC
Vail 5	Efavirenz + PVP K-30	Off white powder	NC	NC	NC	Off white powder	NC	NC	NC
Vail 6	Efavirenz + Lactose	White to Off white powder	NC	NC	NC	White to Off white powder	NC	NC	NC
Vail 7	Efavirenz + Talcum	White to Off white powder	NC	NC	NC	White to Off white powder	NC	NC	NC
Vail 8	Efavirenz + Magnesium Sterates	Off white powder	NC	NC	NC	Off white powder	NC	NC	NC
Vail 9	Efavirenz + SLS	Off white powder	NC	NC	NC	Off white powder	NC	NC	NC

NC=No Change, CCS= Croscarmellose Sodium, SSG= Sodium Starch Glycolate, MCC= Microcrystalline Cellulose, PVP K-30= Polyvinylpyrrolidone, SLS= Sodium Lauryl Sulphate.

Table 2.4: Exicipient Compatibility Study with Efavirenz at 55±2°C

S.No.	Contents	Dry				Wet (with 5% moisture)
		Initial	Day 7	Day 15	Day 21	Initial	Day 7	Day 15	Day 21
Vail 1	Efavirenz	White to Off white powder	NC	NC	NC	White to Off white powder	NC	NC	NC
Vail 2	Efavirenz + CCS	White to Off white powder	NC	NC	NC	White to Off white powder	NC	NC	NC
Vail 3	Efavirenz + SSG	Off white powder	NC	NC	NC	Off white powder	NC	NC	NC
Vail 4	Efavirenz + MCC	Off white powder	NC	NC	NC	Off white powder	NC	NC	NC
Vail 5	Efavirenz + PVP K-30	Off white powder	NC	NC	NC	Off white powder	NC	NC	NC
Vail 6	Efavirenz + Lactose	White to Off white powder	NC	NC	NC	White to Off white powder	NC	NC	NC
Vail 7	Efavirenz + Talcum	White to Off white powder	NC	NC	NC	White to Off white powder	NC	NC	NC
Vail 8	Efavirenz + Magnesium Sterates	Off white powder	NC	NC	NC	Off white powder	NC	NC	NC
Vail 9	Efavirenz + SLS	Off white powder	NC	NC	NC	Off white powder	NC	NC	NC

NC=No Change, CCS= Croscarmellose Sodium, SSG= Sodium Starch Glycolate, MCC= Microcrystalline Cellulose, PVP K-30= Polyvinylpyrrolidone, SLS= Sodium Lauryl Sulphate.

From the results obtained for Drug-excipients compatibility study, it was found that the candidate drug was compatible with the respective excipients under evaluation based on physical observation. So chosen excipients were used in the formulation trails. The result showed that impurity level with drug and some excipients combination increased and also slight change in appearance but all excipients were found compatible with Efavirenz.

3.2.2 Preparation of Efavirenz tablets

Amount of selected complex with excipients i.e. F₁, F₂, F₃, F₄, F₅, F₆ (representing 200 mg equivalent as single dose of drug) was accurately weighted. The weighted as amount was separately mixed with two different concentrations of Croscarmellose sodium and sodium starch glycolate as superdisintegrants, representing six different formulations belong to each type of complex powders. Above mixtures of the complex and croscarmellose and sodium starch glycolate were then blended with directly compressible excipients like magnesium stearate as lubricant, PVP K-30 as binder, magnesium and talc as lubricant, lactose as diluents. Prepared by wet granulation compression were subjected for tableting using 16 station single rotation punch tablet press (Electrical Motor-Crompton Greaves and A.C. Drives-Siemens) to prepare 200mg tablets of Efavirenz. Total numbers of 6 formulations were containing two different superdisintegrant in different concentrations were formulated and coded as F₁, F₂, F₃, F₄, F₅, F₆ , collected in polybags and evaluated for various tablet properties.

3.2.3 Post-Compression Parameters

By using selected mixture, various Wet granulation tablets of Efavirenz had been prepared (F₁, F₂, F₃, F₄, F₅, F₆) and were evaluated for various tablet properties namely-hardness, weight variation, friability, wetting time, water absorption ratio, % drug content, in vitro disintegration time and in vitro drug release. All determinations were carried out in triplicate and the mean of three determinations along with standard deviation have recorded and reported in Table 2.5.

3.2.3.1 Determination of Hardness

Hardness of all the prepared formulations was evaluated using Hardness Tester Model-VHT-1 (HICON^® Grover Enterprises, New Delhi, India). Hardness of all the tablets was found in the range of 9.05±0.30 kg/cm² to 11.00±0.12 kg/cm² as shown in Table 2.5, exhibiting high capacity of the formulations to get mechanically stable during transportation.

Table 2.5 Comparative Results of Various Evaluation Parameters for Prepared tablets

Code	Weight variation	Hardness kg/cm^2	Thickness (mm)	Friability (%)	Disintegration time (min)	Wetting time (Sec)	Water absorption ratio	% Drug content
F1	409±0.46	10.03±0.12	4.01±0.24	0.25±0.14	8.10±0.39	5.43±0.73	1.56±0.02	97.62±0.18
F2	407±0.42	10.02±0.30	4.05±0.22	0.24±0.03	8.35±0.46	5.21±0.54	1.43±0.03	97.13±0.14
F3	409±0.45	11.00±0.12	4.06±0.15	0.23±0.26	8.33±0.43	5.06±0.48	1.59±0.05	98.22±0.18
F4	410±0.48	10.08±0.23	4.02±0.25	0.25±0.02	8.37±0.47	4.56±0.47	1.79±0.03	98.84±0.45
F5	408±0.39	10.06±0.43	4.05±0.31	0.23±0.16	8.40±0.43	5.78±0.56	1.51±0.08	97.73±0.36
F6	410±0.43	9.05±0.30	4.05±0.16	0.24±0.15	8.15±0.42	5.63±0.36	1.46±0.04	97.89±0.46

3.2.3.2 Weight Variation

Prepared tablets were evaluated for weight variation, according to the method described in pharmacopoeia (Indian Pharmacopoeia 1996). From the results obtained as shown in Table 2.5, it can be said all the tablets passed the weight variation test.

3.2.3.3 Friability

Test for friability was conducted according to the method discussed earlier. The result obtained were analyzed and categorized according to the limits given in Pharmacopoeia (Indian Pharmacopoeia 1996) and summarized in Table 2.5.

3.2.3.4 Wetting Time and Water Absorption Ratio

The wetting time of the tablets was measured by using the method described by (Patel et. al., 2004). From the results it had been observed that, the wetting time of prepared formulations (F₁, F₂, F₃, F₄, F₅, F₆) was found to be in the range of 4.56 sec-5.78 sec. Among these formulations F₄ required least time, to get completely wet. Water absorption ratios of all the formulations were also determined and were lies in the range of 1.43±0.03 to 1.70±0.03. It was concluded that the porous structure of complex mixture and superdisintegrants used in the tablet formulation swallowing water to enter the tablet by means of capillary pores, was responsible for the faster water uptake as shown in Table 2.5.

3.2.3.5 Determination of Drug Content

The percentage drug content of all the formulations (F₁, F₂, F₃, F₄, F₅, F₆) was found to be in between 97.13% to 98.84% which was within the acceptable limits (Indian Pharmacopoeia 1996). All the formulations were found to exhibit satisfactory tablet properties as shown in Table 2.5.

3.2.3.6 Disintegration Time

The disintegration time of the all the formulations (F₁, F₂, F₃, F₄, F₅, F₆) was found to be in between 8.10±0.39 min to 8.40±0.43 min which was within the acceptable limits (Indian Pharmacopoeia 1996). All the formulations were found to exhibit satisfactory tablet properties in Table 2.5.

Ultraviolet Absorption Maxima (Scanning): A standard solution of 1µg/ml of Efavirenz powder was prepared in phosphate buffer pH 6.8 solutions and scanned spetrophotometrically (UV-Pharma Spec., Shimadzu) between 200 to 300 nm. The ƛ _max found to be 246 nm.

3.3 Quantitative Estimation of the Drug

3.3.1 Preparation of Calibration Curve of Efavirenz Powder in Phosphate Buffer pH

3.3.1.1 Preparation of Phosphate Buffer pH 6.8: Dissolve 68 g of potassium dihydrogen orthophosphate in 100ml of distilled water and pH 6.8 with sodium hydroxide solution.

3.3.1.2 Preparation of Standard Stock Solution of Efavirenz: Accurately weight 100mg of drug was dissolve in 100ml of phosphate buffer pH 6.8 to give a solution of 100µg/ml. From this 10ml was taken and diluted 100ml using phosphate buffer solution pH 6.8 to get a stock solution of 100µg/ml. From this stock solution various aliquots ranging from 10-50 µg/ml were prepared. The absorbance of these solutions was measured spectrophotometrically at 246nm against reference blank.

3.3.1.3 Preparation of Calibration Curve of Efavirenz in Phosphate Buffer 6.8

Table 2.6: Calibration Curve of Efavirenz in Phosphate Buffer 6.8

Concentration	Absorbance	Statistical Parameters
0	0	Correlation Coefficient r^2= 0.998 Slope M= 0.0278 Intercept c= 0.000 Equation of Line y= 0.0278x-0.000
10	0.057
20	0.115
30	0.165
40	0.224
50	0.282

Figure 1.2: Calibration Curve of Efavirenz

3.3.2 In-vitro Drug Release Studies

The developed tablets were subjected to In-vitro drug release studies in water containing 2% SLS (900ml) employing USP 8 station. Dissolution rate test apparatus (M/S Lab India Disso 8000) with a paddle stirrer at 50 rpm. Sodium Lauryl Sulphate (SLS) was added to the dissolution fluid to maintain the sink condition as prescribed in I.P. 2010. A temperature of 37±0.5°C was maintained throughout the study. Samples of dissolution fluid (5ml) were withdrawn through filter (0.45 µm) at different intervals of time, suitable diluted and assayed for Efavirenz at 246nm. The dissolution fluid withdrawn at each sampling time was replaced with fresh dissolution fluid and suitable correction is made in calculating the amount of drug dissolved. Among all the formulations, the dissolution profile of 2 formulation i.e., formulation F₅ and F₆ are optimized formulation.

Table 2.7: In-vitro Drug Release of Various Formulation of Efavirenz Tablet

Time (min)	% of Drug Release
	F1	F2	F3	F4	F5	F6
0	0.0	0.0	0.0	0.0	0.0	0.0
5	17.98	19.42	33.42	39.63	40.14	50.43
10	36.50	32.86	56.16	57.92	62.84	69.54
15	50.36	50.08	70.13	70.14	78.15	82.18
20	58.45	62.15	76.42	76.29	84.23	89.72
25	60.93	68.12	82.56	82.23	89.98	92.88
30	66.42	72.86	88.19	86.43	90.14	94.23

Figure 1.3: In-Vitro Drug Release of F₁, F₂, F₃, F₄, F₅, F₆ Formulations

3.4 Post Coating Parameters

3.4.1 Disintegration: The disintegration time of the all the formulations (F₁, F₂, F₃, F₄, F₅, F₆₎ was found to be in between 8.30±0.30 min to 8.45±0.42 min which was within the acceptable limits (Indian Pharmacopeia 1996). All the formulations were found to exhibit satisfactory tablet properties.

3.4.2 In-vitro Drug Release Studies:

The developed tablets were subjected to In-vitro drug release studies in water containing 2% SLS (900ml) employing USP 8 station. Dissolution rate test apparatus (M/S Lab India Disso 8000) with a paddle stirrer at 50 rpm. Sodium Lauryl Sulphate (SLS) was added to the dissolution fluid to maintain the sink conditions as prescribed in I.P. 2010. A temperature of 37±0.5°C was maintained throughout the study. Samples of dissolution fluid (5ml) were withdrawn through a filter (0.45 µm) at different intervals of time, suitable diluted and assayed for Efavirenz at 246 nm. The dissolution fluid withdrawn at each sampling time was replaced with fresh dissolution fluid and suitable correction is made in calculating the amount of drug dissolved. Among all the formulations, the dissolution profile of 2 formulation i.e., formulation F₅ and F₆ are optimized formulation.

3.4.3 Differential Scanning Calorimetry:

During the dissolution analyses of Efavirenz tablets, some residue was observed deposited at the bottom of the dissolution vessel, which may have been caused by a change in the crystal packing structure, for example hydrate formation that presented lower solubility and consequently leading to precipitation.

To asses this possible transition, the residues of 3 vessels were separated by filtration and dried in vacuum desiccators and analyzed by XRD and DCS. Figure 3 shows the diffraction patterns of this residue and demonstrates no alteration in the physical conformation in comparison with the diffraction pattern of the pure drug (Figure 1.5).

Table 2.8: In-vitro Drug Release of Various Formulation of Coated Efavirenz Tablet

Time (min)	% of Drug Release
	F1	F2	F3	F4	F5	F6
0	0.0	0.0	0.0	0.0	0.0	0.0
5	17.98	19.42	33.42	39.63	40.14	50.43
10	36.50	32.86	56.16	57.92	62.84	69.54
15	50.36	50.08	70.13	70.14	78.15	82.18
20	58.45	62.15	76.42	76.29	84.23	89.72
25	60.93	68.12	82.56	82.23	89.98	92.88
30	66.42	72.86	88.19	86.43	90.14	94.23

Figure 1.4: In-Vitro Drug Release of F₁, F₂, F₃, F₄, F₅, F₆ Coated Efavirenz Tablet Formulations

Figure 1.5: Diffraction Patterns of Dissolution Residue of Efavirenz

Figure 1.6: Diffraction Patterns Obtained From the Efavirenz Batches 1 to 5 (F₁ to F₅).

Analyses by XRD and DSC were also undertaken in order to evaluate the crystal structure of Efavirenz batches 1 to 5. The DSC curves demonstrate the same thermal profile in all samples tested. The peaks related to crystal melting are at the same temperature and the enthalpies of those peaks are similar. The diffraction patterns of all samples tested have, in the same way, very similar profiles. Therefore, the differences observed in dissolution of the API cannot be attributed to a difference in the crystalline structure of XRD analyses of all batches studied correspond to the structure of efavirenz isoform I, and there is no evidence of the presence of other polymorphs of the drug in those samples. No other transitions were observed, which indicates the absence of amorphous portions in the samples. The peaks corresponding to the structures in the samples were identified. When comparing these results with efavirenz synthesis patent, it can be seen that form I appears to be present in all batches. Therefore, differences in dissolution of the API cannot be attributed to a change in the crystalline structure of the drug (such as polymorphism, hydration or amorphization), but are instead due to the variation of size distribution and polydispersity index that should be controlled in the manufacturing process of the API.

3.4.4 Stability Study:

Stability is defined as the ability of a particular formulation, in a specific container, to remain within its physical, chemical, therapeutic and toxicological specifications.

Table 2.9: Physical and Chemical Parameters of Efavirenz Tablets after 1, 2 and 3 months at 40°C/75% RH

S. No.	Parameter	Initial	1^st month	2^nd month	3^rd month
1	Description	Red shown, capsule shaped with bevelled edges	Red shown, capsule shaped with bevelled edges	Red shown, capsule shaped with bevelled edges	Red shown, capsule shaped with bevelled edges
2	Average weight (mg)	410.7±1.08	409.9±1.05	409.7±1.03	411±1.02
3	Average Thickness (mm)	4.06±0.15	4.05±0.31	4.05±0.16	4.05±0.10
4	Average Hardness	11.00±0.12	10.08±0.23	10.06±0.43	9.05±0.30
5	Average Disintegration Time (min)	3.35±0.46	3.37±0.47	3.33±0.43	3.20±0.42

The purpose of stability testing is to provide evidence on how the quality of a drug substance or drug product varies with time under the influence of a variety of environmental factors such as temperature, humidity and light, and enables recommended storage condition, retest periods and shelf lives to be established. Stability studies were conducted, the drug is subjected to accelerated stability at 40±2°C, 75±5% RH for 3 months. As per the stability results, the formulation exhibits the no notable changes. Efavirenz tablets are stable and comply with that of the specification in the USP

4. CONCLUSION:

Efavirenz film coated tablets were formulated in this research investigation was found to be pharmaceutical equivalent to that of the reference drug. In this research concentration of super disintegrant, granulation technique, lubricants were taken a key role in the formulation development and optimizing the immediate release tablet formulation of Efavirenz. Accelerated stability studies were conducted for the optimized formulation F₁-F₆ as per ICH guidelines; the results were revealed that the formulation exhibit the no notable changes.

Efavirenz, a widely prescribed anti-retroviral drug belongs to class II under BCS and exhibit low and variable oral bioavailability due to its poor aqueous solubility. Its oral absorption is dissolution rate limited and it requires enhancement in the solubility and dissolution rate for increasing its oral bioavailability¹⁸.

Efavirenz (EFV) is nucleoside unrelated compounds which directly inhibit HIV reverse transcriptase without the need for intracellular phosphorylation. Its locus of action on the enzyme is also different. This is more potent than AZT on HIV-2, but do not inhibit HIV-1. Viral resistance to these drugs develops by point mutation and cross resistance is common among different NNRTIs, but not with NRTIs or PLs.

Efavirenz tablets formulated employing drug PVP K-30, SlS, CCS prepared by wet granulation method disintegrated rapidly when compared to those made by direct compression method. Efavirenz dissolution was rapid and higher from the tablets formulated employing PVP K30, SLS when compared to the tablets containing efavirenz alone in both wet granulation and direct compression methods. The individual as well as combined effects of the three factors involved i.e., Croscarmellose sodium (Factor A), PVP K30 (Factor B) and SLS (Factor C) were highly significant (P<0.01) in enhancing the dissolution rate (K1) and dissolution efficiency (DE30) of efavirenz in wet granulation method. All the efavirenz tablets formulated employing drug CCS, PVP K30, SLS are prepared by wet granulation fulfilled the official (I.P.) dissolution rate specification of efavirenz tablets. Whereas plain tablets formulated employing efavirenz alone did not fulfil the official dissolution rate specification. Hence combination of PVP K30, SLS, CCS is recommended to enhance the dissolution rate and efficiency of efavirenz tablets.

In the present study, an attempt has been developed to formulate the coated 600mg efavirenz tablets. For this purpose tablets were developed; composed of a drug along with microcrystalline cellulose, croscarmellose sodium, PVP K30, sodium starch glycolate, lactose, talcum, magnesium stearate, sodium lauryl sulphate as surfactant.

Evaluation of developed formulation for various pre-compression and post-compression parameters was found to be within pharmacopoeia limits.

Pre-Compression Parameters of the Formulation-

Pre-compression parameters were characterized on the basis of their physical parameters. Bulk density (0.337g/ml), Tapped density (0.459g/ml), Compressibility ratio (24.37%), Hausner ratio (1.38)¹⁹.

Post-Compression Parameters-

Weight variation, hardness, and friability pass U.S.P. specification. Tablets of all formulation showed physical appearance, Disintegration test indicated that the tablets of all formulation were dissolved in desire time. Disintegration time of all formulation have to be less than 45 min. Disintegration time of the various formulation were found in following order in min F₅(8.10±0.39)>F₆(8.15±0.42)>F₃(8.33±0.46)>F₂(8.35±0.46)>F₄(8.37±0.47)>F₁(8.40±0.43).

This is due to F₅ and F₆ contain maximum concentration of superdisintegrants (CCS-8.5%, SSG-9.2%), than followed by other formulation. Weight variation tests, hardness and friability test indicated that, tablets of all formulation were having good compactness and mechanical strength and passes U.S.P. specification²⁰.

In-vitro dissolution studies revealed that the release rate of Efavirenz coated tablets were found to be in following order F₆>F₅>F₄>F₃>F₂>F₁. This is due to F₆ contain maximum concentration of superdisintegrants concentration.

5. REFERENCES:

1. VY Rajesh, B Jagdish, Bindu, R Sridev, Swetha Maroju, Ur. Vinay, 2010. Impact of superdisintegrants on efavirenz release from tablet formulations. Acta Pharma; 60(1):185-95.

2. Shirsand SB, Sarasija S, Swamyi PV, Para MS, Nagendra KD. 2010. Formulation Design of Fast Disintegrating Tablets Using Disintegrant Blends. Int J Ph Sci Dec; 72(1):130-3.

3. Jain CP, Naruka PS. 2009 Sep. Formulation And Evaluation of Fast Dissolving Tablets of Valsartan. Int J Ph Sci; 1(1):209-16.

4. American Cancer Society. 2009. Possible Risks of Blood Product Transfusions; 1/13.

5. Institute of Medicine, 1986. National Academy of Sciences. Confronting AIDS; 98.

6. Barghese, B. 2002. Reducing Risk of Sexual HIV Transmission. Sexually Transmitted Diseases; 29(1):39-40.

7. Francis, D.P., 1987. The prevention of acquired immunodeficiency syndrome in the United States. JAMA; 257:1360.

8. Winkelstein, W. 1987. Sexual practices and risk of infection by the human immunodeficiency virus. JAMA; 257:321-325.

9. K.P.R. Chawdary and Annamma Devi, G.S., International Journal of Research in Pharmacy and Chemistry (In press), Manuscript No. IJRPC-254.

10. Schaefer, T.; Holm, P.; Kristensen, H. 1986. Comparison between granule growth in a horizontal and a vertical high speed mixer II. Granulation of lactose, Arch. Pharm. Chemi, Sci. Ed.; 14 (1): 17-29.

11. Schaefer, T.; Holm, P.; Kristensen, H. 1986. Comparison between granule growth in a horizontal and a vertical high speed mixer II. Granulation of lactose, Arch. Pharm. Chemi, Sci. Ed.; 14 (1): 17-29.

12. Ganderton, D.; Hunter, B. 1971. A comparison of granules prepared by pan granulation and by massing and screening. J. Pharm. Pharmacol.; 23: 1S-10S.

13. Shiromani, P.; Clair, J. 2000. Statistical comparison of high-shear versus low-shear granulation using a common formulation. Drug Dev. Ind. Pharm., 26 (3): 357-364.

14. Visavarungroj, N.; Remon, J. 1991. Crosslinked starch as binding agent III. Granulation of insoluble filler. Int. J. Pharm.; 69: 43-51.

15. Sheskey, P.; Williams, D. 1996. Comparison of low-shear and high shear wet granulation techniques and the influence of percent water addition in the preparation of a controlled-release matrix tablet containing HPMC and a high-dose, highly water-soluble drug. Pharm. Technol.; 20(3): 80-92.

16. Chen, C.; Alli, D.; Igga, M.; Czeisler, J. 1990. Comparison of moisture-activated dry granulation process with conventional granulation methods for sematilide hydrochloride tablets. Drug Dev. Ind. Pharm.; 16 (3): 379-394.

17. Railkar, A.; Schwartz, J. 2000. Evaluation and comparison of a moist granulation technique to conventional methods. Drug Dev. Ind. Pharm.; 26(8): 885-889.

18. Viana, M.; Caramigeas, E.; Vachon, M.: N’ Dri, B.; Chulia, D. 2000. Effect of formulation excipients and the manufacturing process for solid dosage form on the initial dissolution of theophylline. STP Pharma Sci.; 10 (5): 363-371.

19. Gao, J.; Jain, A.; Motheram, R.; Gray, D.; Hussain, M. 2002. Fluid bed granulation of a poorly water soluble, low density, micronized drug: comparison with high shear granulation. Int. Pharm.; 237:1-14.

20. Li, J.; Rekhi, G.; Augsburger, L.; Shangraw, R. 1996. The role of intra- and extragranular microcrystalline cellulose in tablet dissolution. Pharm. Dev. Technol.; 1 (4): 343-355.

Received on 08.07.2015 Accepted on 05.08.2015

© Asian Pharma Press All Right Reserved

Asian J. Res. Pharm. Sci. 5(3): July-Sept.; Page 153-167

DOI: 10.5958/2231-5659.2015.00024.7