1. ORAL DRUG DELIVERY SYSTEM

Among the various routes of drug delivery, oral route is the most preferred route¹ which is widely used for the systemic delivery of drugs of different dosage form. Traditional drug delivery system (DDS) has been characterized by immediate release and repeated dosing of the drug, which might lead to the risk of dose fluctuation². So, Sustained Release (SR) dosage forms are designed to release a drug at a predetermined rate by maintaining a constant drug level for a specific period of time with minimum side effects³. SR dosage form is also able to target the drug to specific organ⁴ by using carriers or chemical derivatives to deliver drug to a particular target cell type⁵.

1.1 LIMITATIONS OF CONVENTIONAL ORAL DOSAGE FORM¹

1. A drug with short biological half-life requires successive administration increasing the chances of missing the dosage form leading to poor patient compliance,

2. The drug level may fluctuate in see-saw way, leading to either below effective range or over the effective range,

3. Multiple drug therapy increasing the risk of toxicity as well as overall cost of treatment,

4. The drug levels may raise and fall, which can cause accumulation of adverse effects especially for drugs having less therapeutic index.

2. SUSTAINED RELEASE DRUG DELIVERY SYSTEM (SRDDS)

SR dosage forms are designed to achieve a prolonged therapeutic effect by continuously releasing medication over an extended period of time after administration of single dose. The main aim of SR formulations is to modify and improve the drug performance by increasing the duration of drug action, decreasing the frequency of dosing, decreasing the required dose employed and providing uniform drug delivery⁶. Sustained release formulation maintains a uniform blood level of drug with better patient compliance as well as increased efficacy of drug.

       
           
       
Figure 1: Plasma drug concentration profile for conventional release, a sustained release and zero order controlled release formulation²

2.1 RATIONAL FOR DEVELOPING OF SRDDS⁷

• To extend the duration of action of the drug,
• To sustain the release of drug which provides availability of a drug at action site throughout the treatment in order to improve clinical efficiency of a drug molecule,
• To minimize dosing frequency,
• To reduce cost of treatment by reducing number of dosage requirement
• To minimize toxicity due to overdose which is often in conventional dosage form,
• To enhance the activity duration of a drug possessing short half-life.

2.2 PRINCIPLE OF SRDDS⁸

The conventional dosage forms release their active ingredients into an absorption pool immediately. The absorption pool represents a solution of the drug at the site of absorption. K_r, K_a and K_e are first order rate-constant for drug release, absorption and overall elimination respectively. Immediate drug release from a conventional dosage form implies that K_r >>>> K_a. For non-immediate release dosage forms, K_r <<< K>a i.e. the release of drug from the dosage form is the rate limiting step.

       
           
       
Figure 2: Release of drug from conventional dosage form⁸

The main aim of designing SRDDS is to deliver the drug at a rate necessary to achieve and maintain a constant drug blood level. This implies that rate of delivery should be independent of amount of drug remaining in the dosage form and constant over time, which indicates drug release from the dosage form follows the zero order kinetics, expressed by the equation :-

K_{r °} = Rate In = Rate Out = K_e C_d V_d

Where,

K_r°: Zero-order rate constant for drug release-Amount/time,

K_e: First-order rate constant for overall drug elimination-time,

C_d: Desired drug level in the body – Amount/volume,

V_d: Volume space in which the drug is distributed in liter

       
           
       
Figure 3: Release of drug from non-immediate release formulation⁸

2.3 Classification Of Modified-Release Dosage Forms         

       
           
       
Figure 4: Classification of modified-release dosage forms⁴

1. Extended release dosage forms. (eg. sustained release dosage forms, controlled release dosage forms)

2. Delayed release dosage forms (eg. enteric coated tablets)

3. Targeted release dosage form

2.3.1 Modified Release Dosage Forms

As per USP, it is a dosage form which has drug release characteristics based on time, course or location. Also this dosage form is sufficiently controlled to provide periods of prolonged therapeutic action following each administration of a single dose.

2.3.2 Extended Release Dosage Form⁹         

 It is a dosage forms which releases the drug slowly so that plasma concentration is maintained at a therapeutic level for a period of time.

2.3.3 Delayed Release Dosage Form¹⁰

It is a dosage form which indicates that the drug is not being released immediately following administration but at a later time, eg. Enteric coated tablets.

2.3.4 Prolonged Release Dosage Form¹⁰                                                                                                                   

It is a dosage form which is designed to deliver a dose of a medication over an extended period.

2.3.5 Sustained Release Dosage Form

It is a dosage form which releases an initial amount of drug which is sufficient to provide a therapeutic effect and then a gradual release of drug over an extended period of time.

3. ADVANTAGES OF SUSTAINED RELEASE DRUG DELIVERY SYSTEM¹¹

1. Helps in reduction of frequency of drug administration.

2. Reduces fluctuation in circulating drug levels due to multiple dosing.

3. Produces more uniform effect by reducing blood level variations due to multiple dosing.

4. Shows better drug absorption as the high blood level peaks observed after administration of high dose of drug are reduced.

5. Reduction in GI irritation and other side effects.

6. Reduces the total amount of drug administration, thus

• Maximizes the availability of drug at minimum dose,
• Eliminates the local side effects,
• Reduces systemic side effects,
• Reduces drug accumulation.

7.  Increased and improved patient convenience and compliance.   

8. Economical for patients as it reduces health care cost.

4. Disadvantages Of Sustained Release Dosage Forms

1. Decreased systemic availability which may be due to

• Incomplete release of drug,
• Increased first-pass metabolism, increased instability
• pH dependant solubility,

2. Poor in vitro-in vivo correlation,

3. Increased chances of dose dumping,

4. Retrieval of drug is difficult if toxicity, poisoning, or hypersensitivity reactions occurs,

5. Higher cost of formulation.

5. Characteristics Of Drug Suitable For Sr¹²

5.1 Biopharmaceutic Properties Of A Drug

The performance of a drug presented as controlled release systems depends upon its:

• Release from formulation
• Movement within body during its passage to the site of action

The former depends upon the fabrication of the formulation and physicochemical properties of

drug while the latter element is dependent upon pharmacokinetics of drug. The rate determining

step in the availability of a drug from controlled delivery system is the rate of release of drug

from the dosage form.

       
           
       
Figure 5: Scheme representing the rate limiting step in design of controlled release drug delivery system¹³

A) Molecular Weight Of The Drug

Lower is the molecular weight of the drug, faster and more complete is the absorption.  Molecular size threshold is 150 Daltons for spherical compounds and 400 Daltons for linear compounds. However, more than 95% of drugs are absorbed by passive diffusion. Drugs with large molecular size are poor candidates for oral controlled release system.

B) Aqueous Solubility Of The Drug

A drug with pH independent good aqueous solubility is considered good candidate for controlled release dosage form. The lower limit of solubility of a drug to be formulated as controlled release drug delivery system is 0.1 mg/ml. Drugs with pH dependent aqueous solubility or drugs with solubility in non-aqueous solvents are considered suitable for parenteral controlled release dosage form.

C) Apparent Partition Coefficient Of The Drug               

Greater the apparent partition coefficient of the drug, greater is its lipophilicity and thus, greater is its rate and extent of absorption.

       
           
       
Figure 6: A relationship between drug action and partition coefficient¹⁴

D) Drug pKa And Ionization At Physiological pH

Drugs which exist largely in an ionized form are poor candidates because ionized form of drug is absorbed 3-4 times less than that of the unionized drug. The unionized form of drug is absorbed well.

E) Drug Permeability

The three major drug characteristics which determine permeability of drugs for passive transport across intestinal epithelium are:

• Lipophilicity,
• Polarity of drug  measured by number of H-bond acceptors and number of H-bond donors on the drug molecule,
• Molecular size.

F) Drug Stability   

Drugs which are unstable in GI environment are not administered as oral controlled release formulations due to bioavailability problems. So, different route of administration should be selected. On the other hand, drug unstable in intestine can be formulated as gastro-retentive dosage form.

G) Mechanism And Site Of Absorption

Drugs which are absorbed by carrier-mediated transport processes and those absorbed through a window are poor candidate for controlled release systems.

H) Biopharmaceutic Aspects Of Route Of Administration

Oral and parenteral (i.m) routes are the most popular followed by transdermal route. Routes of minor importance in controlled drug delivery are buccal/sublingual, rectal, nasal, ocular, pulmonary, vaginal and intrauterinal.

5.2 Pharmacokinetic Characteristics Of A Drug In Design   Of Controlled Release Drug Delivery System

ADME i.e Absorption, Distribution, Metabolism and excretion characteristics of drug are essential in design of controlled release product. An optimum range of a given pharmacokinetic parameter of a drug is necessary beyond which controlled delivery is difficult or impossible.

1. Absorption Rate      

A drug with slow absorption is a poor candidate as continuous release will result in a pool of unabsorbed drug. Aqueous soluble but poorly absorbed potent drugs are also poor candidates. Drug to be administered as controlled release formulation, its absorption must be efficient as the rate-limiting step is rate of drug release.

b) Elimination Half-Life

An ideal controlled release drug delivery system is the one where rate of absorption is equal to the rate of elimination. Smaller is the t_1/2, larger the amount of drug is required to be incorporated in the controlled release dosage form. Drugs with half-life in the range of 2 to 4 hours are the good candidates for such system.

c) Rate Of Metabolism  

Drugs which are extensively metabolized are considered suitable for controlled release system as long as the rate of metabolism is not too rapid. Drugs which are capable of inducing or inhibiting metabolism are considered poor candidate.

d) Dosage Form Index (Di)

It is defined as the ratio of C_ss,max to C_ss,min. Since the goal of controlled release formulation is to improve therapy by reducing the dosage form index while maintaining the plasma drug levels within therapeutic window, ideally, its value should be as close to one as possible.

e) Absorption Window

The drugs which show absorption from the specific segment in GIT are a poor candidate for CRDDS. Drugs which absorbed throughout the GIT are good candidates for controlled release.

       
           
       
Figure.7: Absorption window¹⁵

5.3 Pharmacodynamic Characteristics Of A Drug In Design Of Controlled Release Drug Delivery System¹³

 a) Drug Dose

In general, dose strength of 1.0 g is considered maximum for a controlled release drug delivery system.

b) Therapeutic Range

A candidate drug for controlled release drug delivery system have a therapeutic range wide enough such that variations in the release rate do not result in a concentration beyond this level.

c) Therapeutic Index (Ti)

The release rate of a drug with narrow therapeutic index should be such that the plasma concentration attained is within the therapeutically safe and effective range.

Therapeutic index = TD₅₀ ? ED₅₀

Where,

TD₅₀ - Median toxic dose

ED₅₀ - Median effective dose

d) Plasma Concentration Response (PK/PD) Relationship

 Drugs whose pharmacological activity is independent of its concentration are poor candidates for controlled release systems.

Table1: Factors in the design of CRDDS

6. Drug Release From Polymers¹⁷

6.1 Drug Release From Hydrophilic Matrix

Hydrophilic matrix systems are polymer based drug delivery systems where two competing drug release mechanism are involved: Fickian diffusion release and relaxational release. The primary rate controlling materials are polymers on hydration swell rapidly in an aqueous medium and forming a gel layer on the surface. Diffusion across the gel layer is not the only drug release pathway, as erosion of the matrix following polymer relaxation also contributes to release of drug.

6.2. Drug Release From Hydrophobic Matrix

In this system, the drug is dispersed throughout a matrix. For a homogenous monolithic matrix system, the release behavior can be described by the Higuchi equation.

       
           
       
Figure 8: Release of drug from hydrophilic and hydrophobic matrix

7. Kinetics of drug release¹⁷

7.1 Zero Order Kinetics                                

Drug dissolution from pharmaceutical dosage form that does not disaggregate and drug release in slow manner represented by,

W₀-W_t =K_o t

 Where,

 W₀ =Initial amount of drug concentration in solution.

 W_t = Amount of drug release dissolved in time t.

 K₀ t= Zero order rate constant.

When the graph is plotted as cumulative % drug release verses time, if the obtained plot is linear then data obeys zero order kinetics with slope equal to K₀. This model represents an ideal release profile in order to achieve the prolonged pharmacological action.

7.2 First Order Kinetics                                  

Release of drug expressing in this model:

Log Q_t = (Log Qo+ K₁t)/2.303                                                   

 Q_t=Amount of drug release in time t.

Q₀=Initial amount of drug in solution.

K₁t =First order release rate constant.

When data was plotted as log cumulative % drug remaining verses time yields a straight line indicating that the release follows first order kinetics. The constant K can be obtained multiplying slope values.

7.3 Korsmeyer Peppas Model

In 1983 Korsmeyer-peppas developed a simple, semi-empiric model, when diffusion is the main drug release mechanism, relating exponentially the drug release to the elapsed time (t).

A_t/A= ktn

Where,

 k = Constant.

n =Release.

t = Time.

A_t and A_?= Absolute cumulative amount of drug released at time (t)

7.4 Higuchi Model

 Drug release from the matrix device by diffusion has been described by Higuchi’s 

Diffusion equation:

 ft = Q = ?D?/? (2C- ?Cs)Cst

Where,

Q = Amount of drug released in time t.

D = Diffusion coefficient of the drug in the matrix.

Cs = Solubility of the drug in the matrix.

?= Porosity of matrix.

?= Tortuosity.

t = Time (h).

The equation may be simplified then equation becomes;

f_t = Q = KHXt_1/2

Where,

 KH = Higuchi dissolution constant.

t = Time (h).

When data was plotted according to this equation, i.e. cumulative drug released verses square root of time, yields a straight line, indicating that the drug was released by diffusion mechanism.

8. Mathematical Models For Controlled Release Systems

Drug release mechanism and kinetics are the two important characteristics of a delivery system for describing the dissolution profile. Various mathematical models have been developed to analyze drug release from different types of controlled release drug delivery system.

The Korsmeyer- Peppas Power law equation predicts that the fractional release of drug is exponentially related to the release time and this adequately describes the release of drug from slabs, cylinders or spheres.

Table 2: Mathematical Models used to describe drug release kinetics from various matrices

Where,

a = scale parameter,

b = surface parameter,

ft = fraction of dose released at time t

K, K_H, K₀, K_s = release rate constants characteristics to respective models,

m and n = release exponents,

M_t = amount released at time t,

M_? = amount released at infinite time,

Q_o = drug amounts remaining to be released at zero hour,

Q_t = drug amounts remaining to be released at time t,

T_i = lag time before the onset of dissolution,

W_o = initial amount of drug present in the matrix,

W_t = amount of drug released at time t.

A plot of the log (drug released) vs log (time) yields slope n (diffusion exponent) having value-

• n = 0.5 indicating pure Fickian diffusion
• n = 0.5 -1 or n = 0.45-0.89 indicating anomalous non-fickian diffusion i.e the rates of solvent penetration and drug release are in the same range. This deviation is due to increased drug diffusivity from the matrix by solvent-induced relaxation of the polymers.
• n = 0.89 or n = 1 indicates zero-order release which can be achieved when drug diffusion is rapid compared to the constant rate of solvent-induced relaxation and swelling in the polymer.

Table 3: Diffusional Exponent n and mechanism of diffusional release from swellable controlled release systems of different geometrics¹³

II. Material And Methodlogy

9. Preformulation studies

Pre-formulation studies were carried as per standard procedure mentioned in Indian Pharmacopoeia, 2010.

9.1 Characterization Of Aceclofenac

9.1.1. Organoleptic Properties

The colour, odour and taste of the drug were recorded using descriptive terminology¹⁸.

9.1.2 Loss On Drying (Lod)                            

Loss on drying is the loss of weight expressed as percentage w/w resulting from water and volatile matter of any kind that can be driven off under specified condition. The test can be carried out on the well mixed sample of the substance¹⁸.                                                                

LOD = --------------------------------------------------------------------------- x 100

                             Initial weight of substance

The solubility of drug was recorded by using various descriptive terminology specified in Indian Pharmacopoeia, 2007¹⁸.

9.1.4 Melting Point                                        

Melting point of drug sample was determined by using melting point apparatus. A few quantity of drug sample was taken and placed in a thin walled capillary tube; the tube was approximately 10-12 cm in length with 1mm in diameter and closed at one end. The capillary which contain sample was placed in melting point apparatus and heated and when drug sample was melted the melting point of sample powder was noted. ¹⁸

9.1.5 Partition Coefficient                             

­10 mg drug was added in 50 ml of n-Octanol (pre saturated with water) and it was shaken and then 50 ml of distilled water (pre saturated with n- Octanol) was added and was shaken the mixture by mechanical shaker for 24 hours. After 24 hour both phases are separated. Absorbance was taken of both the phases and calculated the concentration in each phases¹⁸.

Po/w =    C _{oil /} C _water

9.2 Physical Evaluation Of Powder

The powder was evaluated for angle of repose, bulk density, tapped density, compressibility index and Hausner ratio.

9.2.1 Bulk Density:

An accurately weighed quantity of the powder (W) was carefully poured into the graduated cylinder and the volume (V_o) was measured then the graduated cylinder was closed with lid, set into the bulk density determination apparatus. The density apparatus was set for 500 taps and after that, the volume (V_f) was measured and continued operation till the two consecutive readings were equal. The bulk density and tapped density were calculated using the following formula:

Bulk density = W/V_o

Tapped density = W/V_f

Where,

V_o = Initial Volume

  V_f = Final Volume

9.2.2 Compressibility Index:

The compressibility index may be calculated using measured values for bulk density (? _bulk) and tapped density (? _tapped ) as follows :

Compressibility index = (? _tapped - ? _bulk )x 100 / ? _tapped

Table 4: Compressibility index limits

9.2.3 HAUSNER’S RATIO:

It is the ratio of volume of tapped volume is tapped density to bulk density.                                         

Hausner’s ratio = ? _{tapped /} ? _bulk

Table 5: Hausner’s Ratio index limits

9.2.4 Angle Of Repose

Angle of repose is defined as the maximum angle possible between the surface of a pile of the powder and the horizontal plane. The static angle of repose was measured using a funnel which was clamped with its tip 2cm above a graph paper, placed on a flat horizontal surface. The powder was carefully poured through the funnel until the apex of the cone thus formed just reached the tip of the funnel. The mean diameters of the base of the powder cones were determined and the tangent of the angle of repose calculated using the equation:

Tan ? =  h /   r

Where,

h = height of pile

r = radius of the base of the pile

? = angle of repose

Table 6: Angle of Repose Limits

9.3 Analytical Method

I. By Using Hydrochloric Acid Buffer Ph 1.2

9.3.1 Determination Of Absorption Maxima

Weighed 10 mg of Aceclofenac and dissolved in 10 ml of Hydrochloric acid buffer pH 1.2  solution (1000?g/ml). From this solution 1ml was taken and diluted to 10ml with HCl buffer pH 1.2  to get a solution containing 100?g/ml. From this 1ml was diluted to 10ml to get working standard solutions of 10?g/ml. This solution was scanned between 200-400 nm and an absorption maxima was determined and compared with literature value.

• PREPARATION OF STANDARD CURVE OF ACECLOFENAC

100 mg equivalent weighed of Aceclofenac was dissolved in 100 ml of Hydrochloric acid buffer pH 1.2. The 10 ml of above solution was further diluted upto 100 ml with Hydrochloric acid buffer pH 1.2. The resulting solution was serially diluted with Hydrochloric acid buffer pH 1.2 to get drug concentration 5, 10, 15, 20, 25 ?g/ml. The absorbance of the solutions was measured against Hydrochloric acid buffer pH 1.2 as a blank using double beam UV visible spectrophotometer. The plot of absorbance v/s concentration (?g/ml) was plotted and data was subjected to obtain linear regression analysis.

II. BY USING PHOSPHATE BUFFER Ph 6.8

9.3.2 DETERMINATION OF ABSORPTION MAXIMA IN PHOSPHATE BUFFER 6.8

Weighed 10 mg of Aceclofenac and dissolved in 10 ml of pH 6.8 phosphate buffer solution (1000?g/ml). From this solution 1ml was taken and diluted to 10ml with PBS to get a solution containing 100?g/ml. From this 1ml was diluted to 10ml to get working standard solutions of 10?g/ml. This solution was scanned between 200-400 nm and an absorption maxima was determined and compared with literature value.

• PREPARATION OF STANDARD CURVE

100 mg equivalent weighed of Aceclofenac was dissolved in 100 ml of phosphate buffer pH 6.8. The 10 ml of above solution was further diluted upto 100 ml with phosphate buffer pH 6.8. The resulting solution was serially diluted with phosphate buffer pH 6.8 to get drug concentration 5, 10, 15, 20, 25?g/ml. The absorbance of the solutions was measured against phosphate buffer pH 6.8 as a blank using double beam UV visible spectrophotometer. The plot of absorbance v/s concentration (?g/ml) was plotted and data was subjected to obtain linear regression analysis.

9.4 Compatibility Testing Of Drug With Polymer:

The proper design and formulation of a dosage form requires consideration of the physical, chemical and biological characteristics of all drug substances and excipients to be used in the fabricating the product. Each polymer used in the formulations was blended with the drug levels that are realistic with respect to the final dosage form. Each polymer was thoroughly blended with drug to increase drug - polymer molecular contacts to accelerate the reactions if possible.

 9.4.1 Fourier Transform Infra-Red (FTIR) Spectroscopy:

FTIR study was carried out to check compatibility of drug with polymers. Infrared spectrum of Aceclofenac was determined on Fourier transform Infrared Spectrophotometer using KBr dispersion method. The base line correction was done using dried potassium bromide. Then the spectrum of dried mixture of drug and potassium bromide was run followed by drug with various polymers by using FTIR spectrophotometer. The absorption maximums in spectrum obtained with the substance being examined correspond in position and relative intensity to those in the reference spectrum.

9.5 Formulation Of Aceclofenac Sustained Release Matrix Tablets                                  

Table 7: Composition of Aceclofenac matrix tablets

9.5.1 Preparation of Tablets by Direct Compression method¹⁹

Preparation of Sustained Release Tablets of Aceclofenac

All SR tablets were prepared by direct compression method. Accurately weighed amounts of drug, polymer and diluent were mixed geometrically in a mortar. This mixture was then passed through Sieve No.40 and thoroughly mixed in a polybag for 15 minutes. The powder blend was then lubricated with magnesium stearate and talc for 2 minutes and compressed into tablets on a rotary tableting machine. The drug polymer ratio was developed to adjust drug release and to keep total weight of tablet constant for all the fabricated batches under experimental conditions of preparations. The total weight of the matrix tablets was 350mg with different drug polymer ratios. The various polymers used were HPMC E15, Guar Gum and HPMC K4M. Diluent like MCC was used for the preparation of matrix tablets.

9.6 Evaluation Of Sustained Release Matrix Tablet Of Aceclofenac

9.6.1. Appearance                                          

The tablets were visually observed for capping, chipping, and lamination²⁰.

9.6.2. Thickness

The thickness of tablets is important for uniformity of tablet size. The thickness of the tablets was determined using a vernier caliper. Ten tablets from each type of formulation were used and average values were calculated²⁰.

9.6.3. Weight Variation Test

For weight variation, 20 tablets of each type of formulation were weighed individually on an electronic balance, average weight was calculated and individual tablet weight was then compared with the average value to find out the deviation in weight²¹.

Table 8: Specifications of %Weight variation allowed in tablets as per IP

9.6.4. Hardness

For each type of formulation, the hardness value of 10 tablets was determined using Monsanto hardness tester.

9.6.5. Percentage Friability

Friability is the measure of tablet strength. This test subjects a number of tablets to the combined effect of shock abrasion by utilizing a plastic chamber which revolves at a speed of 25 rpm, dropping the tablets to a distance of 6 inches in each revolution. A sample of pre-weighed tablets was placed in Roche friabilator which was then operated for 100 revolutions. The tablets were then de-dusted and reweighed. A loss of less than 1 % in weight is generally considered acceptable. Percent friability (% F) was calculated as follows²⁰.

%F = [(Initial Weight - Final Weight) / Initial Weight]  X 100

9.6.6 Content Uniformity:

Content uniformity was determined by accurately weighing 20 tablets and crushing them in mortar with the help of a pestle. Then an accurately weighed quantity of powder equivalent to 25 mg of drug was transferred to a 50 ml volumetric flask. Then added few ml of methanol and made volume upto 50ml with methanol. The solution was filtered through whatmann filter paper. 5 ml of the filtrate was diluted to 50 ml with Methanol. Then 3 ml of the resulting solution was again diluted to 10 ml with Methanol. The absorbance of the resulting 15 µg/ml solution was recorded at 274nm²¹.

9.6.7. In-Vitro Dissolution Studies:

The in-vitro dissolution studies were performed using USP type I dissolution apparatus at 100rpm. Dissolution test was carried out for a total period of 12 hours using Hydrochloric acid buffer (pH 1.2) solution (900 ml) as dissolution medium at 37° ± 0.5° for first 2 hours and Phosphate buffer (pH 6.8) solution (900 ml) for the rest of the period .An aliquot (5ml) was withdrawn at specific time intervals and absorbance was determined by U.V. spectrophotometer at 274 nm. The release studies were conducted in triplicate²².

9.6.8 Kinetic Study:                                       

To describe the Aceclofenac release kinetics from individual tablet formulations, the corresponding dissolution data were fitted in various kinetic dissolution models: Zero order, first order, Higuchi and Korsmeyer–Peppas. The release of drugs from the matrix tablets can be analyzed by release kinetic theories^22,23.

To study the kinetics of drug release from matrix system, the release data was fitted into

• Zero order as cumulative amount of drug release versus time ,
• first order as log cumulative percentage of drug remaining versus time,
•  Higuchi model as cumulative percent drug release versus square root of time,
•  To describe the release behavior from the polymeric systems, data were fitted according to well-known exponential Korsmeyer–Peppas equation as log cumulative percent drug release versus log of time equation.
• Zero Order Kinetics                          

Qt=K₀t                                                             

Where,

Q = Amount of drug release in time t

K₀ = Zero order rate constant expressed in unit of concentration/time

t = Release time

Here, the data was plotted as cumulative percent drug release versus time; if the plot obtained is linear then the data obeys zero-order release kinetics and slope equals K.

• First Order Kinetics

Log Q = Log Q₀-k_t/2.303

Where,

Q₀ = is the initial concentration of drug

k = is the first order rate constant

t = release time

• Higuchi Kinetics

Q=k_t1/2

Where,

k = release rate constant

t = release time, hence the release rate is proportional to the reciprocal of the square root      of time. When the data was plotted as cumulative drug released versus square root of time, yielded a straight line, indicating that the drug was released by diffusion mechanism. The slope equals K.

• Korsmeyer–Peppas

This equation is used to determine the release behavior from controlled release polymer matrix system. The equation is also called as power law,

Mt/M? = Kt n

Where,

Mt = amount of drug released at time t

M? = amount of drug released after infinite time

Mt/M? = fraction solute release

t = release time

K = kinetic constant incorporating structural and geometric characteristics of the polymer system

n = diffusional exponent that characterizes the mechanism of the release of traces. The  magnitude of the release exponent “n” indicates the release mechanism (i.e., Fickian diffusion, non-Fickian, supercase II release). For matrix tablets, values of n of near 0.5 indicate Fickian diffusion controlled drug release, and an n value of near 1.0 indicates erosion or relaxational control (case II relaxational release transport, non-Fickian, zero order release). Values of n between 0.5 and 1 regarded as an indicator of both diffusion and erosion as overall release mechanism commonly called as anomalous release mechanism. When the data was plotted as Log of drug released versus Log time, produced a straight line with a slope equal to n and the K was obtained from Y – intercept.

III.Result And Discussion

10. Preformulation Parameters

10.1 Characterization Of Aceclofenac

10.1.1 Organoleptic Properties

As per the I.P, Aceclofenac exists as crystalline, odourless powder which is white in colour and slightly bitter in taste. Organoleptic properties of drug sample were found similar to that of standard and are given in Table 9.

Table 9: Organoleptic properties of Aceclofenac

10.1.2 Loss On Drying

The percentage loss on drying for Aceclofenac was found to be 0.28%, which comply with given literature value.

10.1.3 Solubility Studies

The available literature on solubility profile of Aceclofenac indicated that the drug is freely soluble in acetone, methanol and practically insoluble in water. The results of Aceclofenac solubility in various media are given in table 5.2. Aceclofenac showed pH dependent solubility. At lower pH, the solubility was less and as the pH was raised from acidic to 6.8 and 7.4 its solubility drastically improved²⁴

Table 10: Solubility of Aceclofenac in different solvents

10.1.4 Melting Point Determination

The reported melting point of Aceclofenac is 158° C. The observed melting point values of Aceclofenac sample was found to be 156.7° C +0.36 (n=3), which is nearby to reported value. From the determination of melting point, the drug was identified as Aceclofenac.

Table 11: Melting point of Aceclofenac

10.1.5 Partition Coefficient

 The study showed that major portion of drug was partitioned towards organic phase which indicates lipophilicity of the compound and higher absorption of the compound occurs through lipoidal cell membrane. This also signifies that drug belongs to BCS class II (low solubility and high permeability).

10.2 Physical Evaluation Of Powder

Aceclofenac raw material showing passable flowability This reveals that all the formulation blend have good flow characteristics and flow rate. Degree of compression is characteristic of compression capability of the powder and the results obtained exhibit good compression property of the powder.

Table 12: Physical Evaluation of Aceclofenac powder

N=3, Mean ± S.D

10.3 Analytical Method

10.3.1 ?max Determination:

• In HCl Buffer pH 1.2 :

The absorption maxima for Aceclofenac was found to be 272.5 nm.

       
           
       
Figure 9: ? max observed for Aceclofenac in HCl buffer pH 1.2

•  pH 6.8 :

The absorption maxima for Aceclofenac was found to be 274 nm.

       
           
       
Figure 10: ?max observed for Aceclofenac in Phosphate buffer pH 6.8

10.3.2 Preparation Of Standard Curve Of Aceclofenac

• In HCl Buffer pH 1.2

UV absorption spectrum of Aceclofenac in HCl buffer pH 1.2 shows ?max at 272.5 nm. The data for standard curve of Aceclofenac in HCl buffer pH 1.2 is shown in table 5.4. The standard plot is as shown in figure 5.3. Beer Lambert Law was obeyed over the range of 0-25 ?g /ml and data was found to fit the equation

y = 0.012x+ 0.001                                           

r² = 0.999                                                         

Table 13: Data of concentration and absorbance for Aceclofenac in HCl buffer pH 1.2

       
           
       
Figure 11: Calibration Curve of Aceclofenac in HCl buffer pH 1.2

•  IN PHOSPHATE BUFFER pH 6.8

UV absorption spectrum of Aceclofenac in Phosphate buffer pH 6.8 shows ?max at 274 nm. The data for standard curve of Aceclofenac in buffer pH 6.8 is shown in table 5.5. The standard plot is as shown in figure 5.4. Beer Lambert Law was obeyed over the range of 0-25 ?g /ml and data was found to fit the equation

y = 0.028 + 0.002                                            

r² = 0.999

Table 14: Data of concentration and absorbance for Aceclofenac in Phosphate buffer pH 6.8

       
           
       
Figure 12: Calibration Curve of Aceclofenac in Phosphate Buffer pH 6.8

104. Compatibility Testing Of Drug With Polymer:

10.4.1. Fourier Transform Infra-Red (FTIR) Spectra’s

Table 15: Interpretation of Aceclofenac FTIR Spectra

       
           
       
Figure 13: FTIR Spectra of Aceclofena

FTIR Spectra of HPMC K4M

       
           
       
Figure 14: FTIR Spectra of HPMC K4M

Table 16: Interpretation of FTIR Spectra of HPMC K4M

Table 17: Interpretation of FTIR spectra of Aceclofenac and HPMC K4M

       
           
       
Figure 15: FTIR Spectra of Blend of Aceclofenac and HPMC K4M

10.5 Evaluation Of Sustained Release Tablets Of Aceclofenac

10.5.1 Appearance:

The tablets were observed visually and did not show any defect such as capping, chipping and lamination.

10.5.2 Thickness

Ten tablets were randomly selected from each batch and their thickness was measured by using Vernier Caliper. The thickness of tablets for formulations F1 to F9 is given in Table 18.

10.5.3 Weight Variation Test

A tablet is designed to contain a specific amount of drug. The average weight of the tablet is 350 mg and the pharmacopoeial limit for percentage deviation is ± 5 %. Average weight of tablets for formulations F1 to F9 are mentioned in Table 18.

10.5.4 Tablet Hardness

A difference in tablet hardness reflects difference in tablet density and porosity. Hardness was measured using Monsanto hardness tester. The hardness of tablets was found to be in the range of 6.70 ± 0.54 kg/cm² to 7.09 ± 0.55 kg/cm². This indicates good tablet strength. The observed value of hardness of tablets for formulations F1 to F9 is mentioned in a Table 18.

10.5.5 Percentage Friability

Twenty tablets were weighed and placed in the Roche Friabilator apparatus and were rotated at 100 rpm for 4 minutes. After revolutions, the tablets were de-dusted and weighed again. Percentage friability of all the formulations was found between 0.22 to 0.56%. This indicates good handling property of the prepared SR tablet. The percentage friability of tablets for formulations F1 to F9 is given in Table 18.

 The percentage friability was measured using the formula,

% F = {1- (W_t / W)} x 100

Where

%F = friability in percentage

W = Initial weight of tablet

W_t = weight of tablet after revolution

10.5.6 Drug Content Of Aceclofenac:

The content of active ingredients in the formulation was found to be between 98.67± 1.09 % to 99.81±0.87% w/w, which lies within the specified limit as per Indian Pharmacopoeia 1996, 90-110 % w/w. Drug content in formulations F1 to F9 is given in Table 18.

Table 18: Evaluation tests of Formulations F1 to F9

N=3, Mean ± S.D

10.5.7 In-Vitro Dissolution Studies:

To simulate the pH variation in the GI tract, dissolution studies were performed first in HCl buffer pH 1.2 for 2 hours and later in phosphate buffer 6.8 pH. All the formulations showed very low drug release in HCl buffer pH 1.2. This was due to the very low solubility of Aceclofenac at pH 1.2. The release of the drug is faster in phosphate buffer pH 6.8 than HCl buffer medium.

All the matrix formulations, except F1, did not disintegrate within the 2-hour dissolution test period in pH 1.2 buffer. The disintegration of F1 tablets is probably due to its matrix which consisted of low – viscosity HPMC (E15) which is more soluble than the higher viscosity grades of the polymer. Tablets of formulation F1 to F3 with HPMC E15 shows release rate of 91.34%, 89.75% and 84.46%. Release rate for formulations F4 to F6 is 96.75%, 93.61% and 90.65 % whereas formulations F7 to F9 shows 91.23%, 87.56% and 81.38 % release of drug. Results of dissolution test are mentioned in tables 19, 20 and 21.

Table 19: In-Vitro Dissolution Result of formulations F1 to F3 with HPMC E15 as       polymer

                                                                                    N=3, Mean ± S.D

Table 20: In-Vitro Dissolution Result of formulations F4 to F6 with HPMC K4 as polymer

N=3, Mean ± S.D

Table 21: In-Vitro Dissolution Result of formulations F7 to F9 with Guar Gum as polymer

N=3, Mean ± S.D

       
           
       
Figure 16: In vitro dissolution of formulations F1-F3 with HPMC E15 as polymer

       
           
       
Figure 17: In vitro dissolution of formulations F4-F6 with HPMC K4 as polymer

       
           
       
Figure 18: In vitro dissolution of formulations F7-F9 with Guar Gum as polymer

10.5.8 Kinetic Study

To describe the kinetics of Aceclofenac sustained release tablet, the corresponding dissolution data were fitted in various kinetic dissolution models. The kinetics for Aceclofenac sustained release tablets were examined based on the magnitude of correlation coefficients obtained after application of zero order, first order, Korsemeyer peppas and Higuchi diffusion models. The kinetic analysis of drug release showed the release of drug from formulation in following order: Higuchi > Korsemeyer –Peppas >Zero order, First order. A higher correlation, as indicated by (r²) is observed for the Higuchi matrix release kinetics in most of the formulations suggesting the diffusion as a probable prominent mechanism of drug release.(Manoj Kumar Sarangi et al, 2018)     

The value of correlation coefficient for zero order ranges from 0.946 to 0.997, for first order r² ranges from 0.937 to 0.991. For Higuchi model value of r² limits from 0.989 to 0.996 and for Korsemeyer Peppas plot r² value ranges from 0.983 to 0.996 and value of n varies from 0.735 to 1.025.

Table 22: In-vitro Release Kinetic models for Aceclofenac sustained release Matrix tablets of Formulations (F1 to F9)

For formulation F4, drug release data was best explained by Higuchi equation, as the plots showed the highest linearity (r² = 0.992), followed Korsmeyer-Peppas (r²= 0.991) and first order (r²= 0.963). As the drug release was best fitted in first order kinetics, indicating that the rate of drug release is concentration dependent. Higuchi’s kinetics explains why the drug diffuses at a comparatively slower rate as the distance for diffusion increases.

Mechanism of drug release

As shown in Figure, the corresponding plot (log cumulative percent drug release vs time) for the Korsmeyer-Peppas equation indicated a good linearity (r²= 0.991). The diffusion exponent n was 0.735, which appears to indicate a coupling of the diffusion and erosion mechanism (Anomalous diffusion) and shows that the drug release was controlled by more than one process.

Table 23: Drug Release Kinetics of Formulation (F4) Matrix Tablets