Process Validation and Evaluation of Pegylated Solid

RESEARCH ARTICLE

Process Validation and Evaluation of Pegylated Solid Dispersion of Diclofenac Tablet Nirav S Kansagra1*, Vidhi N Kalola1, Smita V Soriya1, Naisarg D Pujara1, Jagruti P Vaghela1, Ramesh B Parmar1, Parula B Patel1 Abstracts: Pegylated Solid dispersion of diclofenac was prepared to achieve improved bioavailability. Currently only 8 % of new drug candidates have both high solubility and permeability. More than 60 % of potential drug products suffer from poor water solubility. This frequently results in potentially important products not reaching the market or not achieving their full potential. Experience with solid dispersions over the last 20-30 years indicates that this is a very fruitful approach to improving the release rate and oral bioavailability of poorly water soluble drugs. So this article highlights technology various approaches for the preparation of solid dispersion, technology involved, detail description of poorly water soluble drugs & carriers. The purpose of this study is to fabricate the polyethylene glycol matrix tablet by mold technique. Diclofenac and hydroxyl propyl methyl cellulose were used as model drug and polymer, respectively, in PEG matrix system. Scanning electron microscope photomicrograph indicated the drug diffusion outward through the porous network of this developed matrix tablet into the dissolution fluid. Both the enhancement of drug dissolution and the prolongation of the drug release could be achieved for aqueous insoluble drug such as, Diclofenac by using polyethylene glycol-hydroxy propyl methylcellulose matrix system prepared with melting and mold technique.

INTRODUCTION [1, 2] Solid dispersion refers to a group of solid products consisting of at least two different components, generally a hydrophilic matrix and a hydrophobic drug. The matrix can be either crystalline or amorphous. The drug can be dispersed molecularly, in amorphous particles or in crystalline particles. Therefore, based on their molecular arrangement, six different types of solid dispersions can be distinguished. Solid dispersions should preferably be designated according to their molecular arrangement.

size. Thus, a solid solution can achieve a faster dissolution rate than the corresponding eutectic mixture. Solid solutions can be classified by two methods. According to the extent of miscibility of the two components, they may be classified as continuous or discontinuous. In continuous solid solutions, the two components are miscible in the solid state in all proportions. Glass Solutions and Suspensions A glass solution is a homogeneous glassy system in which a solute dissolves in the glassy system. A glass suspension refers to a mixture in which precipitated particles are suspended in a glassy solvent. The glassy state is characterized by transparency and brittleness below the glass transition temperature. Glasses do not have sharp melting point; instead, they soften progressively on heating. The lattice energy, which represents a barrier to rapid dissolution, is much lower in glass solutions than in solid solutions.

Types of Solid Dispersion [1-3] x Simple eutectic mixtures x Solid solutions x Glass solution and suspension x Amorphous precipitations in a crystalline carrier Simple Eutectic Mixtures These are prepared by rapid solidification of the fused melt of two components that show complete liquid miscibility and negligible solid-solid solubility. Thermodynamically, such a system is an intimately blended physical mixture of its two crystalline components. Thus the X-ray diffraction pattern of a eutectic constitutes an additive composite of two components. Ex. Chloremphenicol-urea; Paracetamolurea; x Griseofulvin & Tolbutamide-PEG 2000. x T A– M.P. of solid A x T B – M.P. of solid B x TE – Eutectic Point

Amorphous Precipitations in a Crystalline Carrier The difference between this group of solid dispersions and the simple eutectic mixture is that the drug is precipitated out in an amorphous form in the former as opposed to a crystalline form in the latter. Sulfathiazole was precipitated in the amorphous form in crystalline urea.

Solid Solutions In a solid solution the two components crystallize together in a homogeneous one phase system. The particle size of the drug in the solid solution is reduced to its molecular

Factors Affecting the Solubility Profile [3, 4] x Particle size x Temperature x Pressure x Molecular size x Nature of solute and solvent x Polarity x Polymorphous

S. J. Thakkar Pharmacy College, Rajkot, Gujarat, India. E-mail: [email protected] *Corresponding author

Common Methods Used for Preparation of Solid Dispersion [5, 6] x Fusion method.

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Inventi Rapid: Pharm Tech Vol. 2013, Issue 1 [ISSN 0976-3783]

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2013 ppt 649, CCC: $10 © Inventi Journals (P) Ltd Published on Web 31/12/2012, www.inventi.in

RESEARCH ARTICLE Table 1: Drugs and its Solubility Profile [4-6] S. No.

Drugs

Category Anti inflammatory, Analgesic

1

Ibuprofen

2

Furosemide

Diuretic

3

Gliclazide

Anti Diabetic

4

Glipizide

Anti Diabetic

5

Aceclofenac

6

Indomethacin

7

Diclofenac

Anti inflammatory

Freely soluble in Ethanol, Soluble in Ethanol(95%), Sparingly soluble in water and glacial acetic acid

8

Felodipine

Calcium Channel Blocker

Sparingly soluble in dicromethane, Slighly soluble in ethanol (95 %)

9

Loperamide

Antidiarrheal

Soluble in acetone, Sparingly soluble in ethanol (95 %) and glacial acetic acid Slighly soluble in ethanol (95 %)

10

Ketoprofen

Anti inflammatory, Analgesic

Freely soluble in Acetone, chloroform, ether

11

Morphine

NSIDS

12

Naproxen

Anti inflammatory

13

Nimodipine

14

Ofloxacin

Anti inflammatory, Analgesic Anti inflammatory, Analgesic

Solubility Profile Slightly soluble in water, less than 1 mg dissolve in 1 ml of water (>1mg/ml),more soluble in water methanol mixture. Soluble in acetone, sparingly soluble in ethanol(95 %), slightly soluble in ether Sparingly soluble in dicromethane, Slighly soluble in ethanol (95 %) Soluble in ether, Sparingly soluble in ethanol(95 %),Slightly soluble acetone Practically insoluble in water, Freely soluble in acetone, Soluble in acetone Soluble in chloroform, Sparingly soluble in ethanol (95 %)

Soluble in water, Freely Soluble in hot water, More soluble in hot ethanol Soluble in water, Freely Soluble in hot water, More soluble in hot ethanol

Calcium Channel Blocker Antibiotic

Poorly water soluble drugs Soluble in ethanol and chloroform, Insoluble in ether

Table 2: List of Equipments and Their Uses List of Equipments Porcelain dish Mortar pastle Saizoner mixture granulator Colloidal mill Fluidazied bed dryer Double cone blener Tablet compression machine

Their Uses Hot Melting Dry Mixing Granulation Milling Drying Blending Compression

Table 3: Formula for Solid Dispersion of Diclofenac Sodium Tablet

x x x x x x x x x

S. No.

Ingredient

Function

1. 2. 3. 4. 5. 6. 7. 8

PEG-6000 Diclofenac Sodium Microcrystalline Cellulose Starch Talc Magnesium Stearate Poly vinyl pyrolidine K 30 60% Ethanol

Polymer API(Analgesic) Disintigrant/Diluent Binder/Diluent Glident Lubricants Binder Binder

x x x x

Solvent method. Melting solvent method. Solvent-deposition method. Melt agglomeration process. Solvent evaporation method Crystallization in aqueous solvent Use of adsorbent Kneading Method Supercritical Fluid Method


Quantity/ Tablet (mg) 41.5 125 175 125 2.5 2.5 23.5 5

Quantity/ 10 Tablet (mg) 415 1250 1750 1250 25 25 235 50

Lyophilization method Extruding method Spray drying Electro spinning

Characterization of the Solid Dispersion System [4-6] x Thermal analysis. x Spectroscopic method. x X-ray diffraction method.

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RESEARCH ARTICLE Table 4: Flow Property of Powder Value 5 – 15 12 – 16 18 – 21 23 – 28 28 – 35 35 – 38 >40

Types of Flow Excellent – free flowing granules Good – free flowing powder granules Fair powder granules Poor – very fluid powders Poor – fluid cohesive powder Very poor – fluid cohesive Extremely poor – cohesive powder Table 5: Type of Flow of Powder Hausner’s Ratio 1.5

Type of Flow Good flow Moderate flow Poor flow Table 6: Flow Property of Granules

1 2

Angle of Repose 19.02 19.15

Bulk Density (gm/ml) 0.47 0.46

Tapped Density (gm/ml) 0.58 0.56

Hausner’s Ratio 1.23 1.21

3

20.02

0.47

0.57

1.21

Type of Tablet

Batch No.

Solid dispersion tablet of Diclofenac sodium tablet

Carr’s Index 18.96 17.85 17.54

Table 7: Weight Variation of Solid Dispersion Tablet Tablet Weight(mg) Average Minimum Maximum

Batch No. 1 512.12 510.1 505.01

Batch No.2 518.2 512.32 507.21

Batch No.3 520.08 517.3 510.5

Table 8: Friability of Solid Dispersion Tablet Batch No. 1 2 3

Total No of Tablet to be Tested 10 10 10

Total Weight of Tablet(Initial Weight) 5.12 5.17 5.14

Total Weight of Tablet (After Weight) 5.10 5.16 5.13

Difference in Weight 0.02 0.01 0.01

% Friability of Tablet 0.390 0.193 0.195

Table 9: Hardness Test Hardness of the Tablet Average Maximum Minimum

Batch No.1 5.10 5.6 4.5

Batch No.2 5.12 5.8 4.7

Batch No.3 5.09 5.06 4.6

Table 10: Diameter of the Solid Dispersion Tablet Batch No. 1 2 3

No. of Tablet to be Tested 5 5 5

10 9 10

Tablet Diameter 10 11 9 10 9 10 11 11 10

Mean Diameter of Tablet 10 9.8 10.2

x PEGylation has become a well-accepted method for the delivery of biopharmaceuticals - especially peptide and protein drugs. x Simple modification with polyethylene glycol (PEG) is not only capable of improving the pharmacological properties of a drug but has also to be considered with regard to its life cycle extension.

x Dissolution rate method. x Microscopic method. x Thermodynamic method. x Modulated temperature differential scanning calorimetric x Environmental scanning electron microscopy x Dissolution testing (Table 1 shows drugs and its solubility profile [4-6])


10 11 9

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RESEARCH ARTICLE Table 11: Thickness of the Solid Dispersion Tablet Thickness of the Tablet Average Maximum Minimum

Batch No.1 4.03 4.5 3.6

Batch No. 2 4.04 4.3 3.7

Batch No. 3 4.05 4.4 3.8

Table 12: Assay of Solid Dispersion Tablet Absorbance Concentration For batch No.1 0.24 30 0.39 60 0.54 90 0.68 120 0.77 150 0.86 180

Absorbance Concentration For batch No. 2 0.25 30 0.47 60 0.56 90 0.67 120 0.78 150 0.87 180

Absorbance Concentration For batch no. 3 0.26 30 0.48 60 0.57 90 0.68 120 0.79 150 0.88 180

Table 13: Disintegration of Solid Dispersion Tablet Batch No. 1 2 3

No. of Tablet Tested 5 5 5

4 4 5

Tablet Disintigration Time(min) 3 4 5 4 5 6 4 5 6 3 5 4

Mean Disintegration Time of Tablet 4 4.8 4.6

Table 14: Dissolution of Solid Dispersion Tablet(For Batch No:1)

Time Absorbance 30 60 90 120 180 240

0.292 0.298 0.306 0.310 0.312 0.313

Concentration Concentration Concentration Cumulative Dilution Cumulative of Ions (mg/ml) of Ions (mg/ml) Loss Drug Release of Ions Factor Loss (CDR) in 5 ml in 900 ml (μg/ml)in 9.181 10 0.091 16.527 0 10 16.527 15.545 10 0.155 27.981 0.0918 0.0918 28.073 22.363 10 0.224 40.254 0.155 0.247 40.501 28.727 10 0.287 51.709 0.223 0.470 52.18 32.818 10 0.328 59.072 0.287 0.758 59.830 36.909 10 0.369 66.436 0.328 1.086 67.522

%CDR 16.94 28.78 41.52 53.50 61.34 69.23

Table 15: Dissolution of Solid Dispersion Tablet (For Batch No:2)

Time 30 60 90 120 180 240

Concentration Concentration Concentration Dilution of Ions of Ions Absorbance of Ions Factor (mg/ml) in 5 (mg/ml) in (μg/ml)in ml 900 ml 0.25 9.181 10 0.0918 16.527 0.47 19.181 10 0.191 34.527 0.56 23.272 10 0.232 41.890 0.67 28.272 10 0.282 50.890 0.78 33.272 10 0.332 59.890 0.87 37.363 10 0.373 67.254

Loss

Cumulative Loss

0 0.0918 0.1918 0.2327 0.2827 0.3327

0 0.0918 0.283 0.516 0.799 1.131

Cumulative Drug Release (CDR) 16.527 34.619 42.174 51.407 60.69 68.38

%CDR 16.94 35.49 43.24 52.70 62.22 70.11

Table 16: Over all Summary of the Solid Dispersion Tablet Parameter a. b.

Flow Property Angle of repose Hausner’s Ratio Weight variation Thickness Hardness Friability In vitro Disintegration In vitro Dissolution


Result Less than 25 indicates good flow b. Less than 1.25 indicates good flow All the tablet are within the limit of 98-105 Not more than 10 -12 Greater than 4% Less than 1% Between 13- 21sec 69.23%w/w Diclofenac sodium in 4 Hour a.

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Inference Comply with IP Standard Comply with IP Standard Comply with IP Standard Comply with IP Standard Comply with IP Standard Comply with IP Standard Comply with IP Standard Comply with IP Standard


RESEARCH ARTICLE y = 0.0223x + 0.0398 R² = 0.9998

Abs

1

0.8 Absorbance

Absorbance

0.8 0.6 Abs

0.4

Linear (Abs)

0.2

0.6 Abs

0.4

Linear (Abs)

0.2 0

0 0

10

20

30

0

40

10

y = 0.021x + 0.1009 R² = 0.982

Abs

%CDR

0.6 0.4

Abs

0.2

Linear (Abs)

0 10

20

40

30

y = 0.3534x + 8.1073 R² = 0.9894

80 70 60 50 40 30 20 10 0

0.8

0

30

Figure 2: Calibration curve for batch No.2

Figure 1: Calibration curve for batch No.1 1

20 Concentration

Concentration

Absorbance

y = 0.021x + 0.1009 R² = 0.982

Abs

1

40

%CDR Linear (%CDR)

0

Concentration

Figure 3: Calibration curve for batch No.3

50

100

150

200

Figure 4: % CDR for batch No.1 y = 0.3434x + 10.447 R² = 0.9834

%CDR

80 70

%CDR

60 50 40 30

%CDR

20

Linear (%CDR)

10 0 0

50

100

150

200

Time (min)

Figure 5: % CDR for batch No.2

x PEGylation is the covalent coupling of non-toxic, hydrophilic polyethylene glycol (PEG) to active pharmaceutical ingredients x The technology was developed from pioneering work carried out in the 1950s and 1960s on the coupling of polymers to proteins, and by the 1970s Frank F. Davis was using PEG for protein modifications.

liquid paraffin. Disperse the sample uniformly with the help of a brush. Place the cover slip to avoid entrapment of air bubbles. Drain the excess liquid with a blotting paper. Place the slide on the stage of the microsphere. Focus the slide in low magnification (10 X). Observe the presence of individual particle. Shift to high power (45 X) and focus the slide. Measure the size of each particle in terms of eye-piece divisions. Tabulate the particle in terms of divisions of eyepiece and number of particles. Multiply the number of eyepiece divisions by the calibrated value. Classify the diameters into size ranges and calculate the number of distribution.

Peglylation Concept [7-9] It involves the attachment of PEG (Poly-ethylene Glycol) to therapeutic proteins or small molecules for the purpose of enhancing the therapeutic value. Calibrate the eye piece micrometer and transfer the solid dispersion on clean slide. Add one or two drops of


Advantages [8, 9]

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RESEARCH ARTICLE A longer in-vivo (circulating) half-life especially of smaller peptides and proteins, which normally have a rapid glomerular filtration rate and are cleared on the basis of size. This results in a much less frequent dosing regimen x Reduced immunogenecity and toxicity and prevents neutralizing-antibody formation to certain proteins and therapeutic enzymes. x Protection against proteolysis by forming shell around the protein x Avoidance of reticulo-endothelial (RES) clearance x Reduce clearance rate through the kidneys leading to improved bioavailability. x Improved bioavailability via. reduced losses at subcutaneous injection sites x A low volume of distribution and sustained absorption from the injection site useful for slow release depot administration strategies i.e. Optimized pharmacokinetics resulting in sustained duration x Improved safety profile resulting with lower toxicity, immunogenecity and antigenecity. x Due to the amphiphilic nature of PEG, PEGylation improves formulation properties of the protein i.e. improve the solubility and physical-chemical stability of proteins

x Highly soluble, amphiphilic polyether diol x Does not harm active protein or cells x Molecular weight: Few hundred to approximately 20,000 x High mobility in solutions x It contain two OH-groups that can be activated x Currently, there are two main types of commercially available PEG: Linear and Branched x PEG is a viscous liquid at molecular weights lower than 1000 and solid at higher molecular weights. x Poly-dispersity i.e. Molecular weight distribution is narrow (1.01 – 1.1) Factors Affecting Performance of Pegylated Peptides [14, 15]

x Molecular Weight and Structure x Molecular weight < 1000 Da: broken down into subunits, and have some toxicity. x Molecular weight > 1000 Da: does not demonstrate any toxicity in-vivo. x Molecular weight upto 40,000 – 50,000 Da: used in clinical and approved pharmaceutical application. x The molecular weight of PEG has a direct impact on the activity; higher molecular weight PEGs tends to have lower in-vitro activity but have higher in-vivo activity due to the improved pharmacokinetic profile. x Number of PEG chains x Two or lower molecular weight chains can be added to increase total molecular weight of PEG complex.

Specifications [10, 11] x FDA has approved PEG for use as a vehicle or base in foods , cosmetics and pharmaceuticals x It shows little toxicity and is eliminated by kidneys (for PEGs < 20k Da) or through faeces (for PEGs > 20k Da) x It can produce a decrease in the in-vitro activity of proteins, but generally this negative effect is offset in the biological systems by increased half-life x It lacks immunogenecity, but antibodies to PEG are generated in rabbits; only if PEG is combined with highly immunogenic proteins. x No one has ever reported the generation of antibodies to PEG under routine clinical administration.

METERIAL AND METHODS [14-22] Materials Diclofenac sodium obtained as a gift sample Centurion Laboratories, Vadodara.PEG-6000, PVP K-30, methanol, ethanol & all other materials are obtained through commercial sources. Instrumentation A UV visible spectrophotometer (Shimadzu 1800) with spectral bandwidth 1 nm was employed for all spectroscopic measurements, using a pair of 10 mm matched quartz cells (Table 2).

Mechanism of Action [12, 13] x After administration, when PEG comes in contact of aqueous environment, ethylene glycol sub-unit gets tightly attached to the water molecule. This binding to water renders them high mobility and hydration. x Hydration and rapid motion causes PEGylated protein to function, as it causes PEG to sweep out a large volume which acts like a shield to protect the attached drug from enzymatic degradation and interaction with cell surface proteins. x This increased size also helps to prevent rapid renal filtration and clearance sustaining the drug bioavailability (Figure 1 shows in-vivo mechanism of pegylated formulation)

Formulation of Solid Dispersion Tablets Table 3 shows Formula for Solid Dispersion of Diclofenac Sodium Tablet. Preparation of Solid Dispersion [17, 18] PEG-6000 was dispensed accurately and heated to melt at about 40°C. Add Diclofenac to the melt while hot and keep stirring to make it homogeneous. Then immediately add Microcrystalline Cellulose as adsorbent in porcelain dish. Starch, talc & Magnesium stearate of required quantity was added to the above mixture and mixed for 5 min. Solid dispersion was prepared.

Chemical Properties [13-15] x General formula: HO-(CH2CH2O)n-CH2CH2OH x Inert, non-toxic and non-immunogenic


Preparation of Tablet from Solid Dispersion [17, 18, 22] Now for solid dispersion tablet preparation add polyvinyl pyrolidine as a binding agent and add slowly 60 %

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RESEARCH ARTICLE x x x x x x x x

methanol with continuous mixing till the lump obtained. Lump is passed from the sieve to get desired sized granule. Dry the granule in a hot air oven for 10 min at 30ºC. Further passed through the sieve to obtain small uniform sized granule. Make the tablet of desired sized by tablet punching machine. Evaluation of Solid Dispersion [17-22] Angle of Repose It is the maximum angle possible between tip of pile and horizontal plane and it was measured by fixed funnel method. It was measured by following formula:

Dry Mixing The dry-mixing step involves mixing of active Ingredients with other additives using Saizoner. Mixing speed and mixing time are the critical variables that determine content uniformity. Mixing speed is kept constant, mixing time shall be studied to validate dry mixing step.

tan θ = h/r Flow Property of Powder Given in Table 4.

Fixed Parameters x Time interval studies: 4, 7 & 10 minutes x Measured response: Description, blend uniformity x Acceptance criteria : Not less than 90 % and not more than 110 % of the label claim:

Bulk Density It is the ratio of mass of the blend to bulk volume. It was measured by pouring powder in measuring cylinder and measuring the volume occupied by powder.

Drying Drying the desired LOD will be maintained in the granules which will influence the quality parameters like tablet hardness, flow properties, physical properties during compression. If level of moisture is more in granules then blend will have poor flow & distribution characteristics. If level of moisture in blend is less it will produce tablet with capping, high friability and chipping problems. Analysis: Loss on drying (by Karl Fischer titrimetric method.)

Tapped Density It is the ratio of mass of the blend to tapped volume. It was measured by digital tap densitometer by measuring the volume occupied by powder after 100 standard tapping. Carr’s Index It was measured by below formula Ψ ൌ

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Hausner’s Ratio It was measured by below formula

Blending Purpose of blending is to get a uniform distribution of API. Mixing speed and time are critical variables in this process.

H.R= Tapped density/Bulk density

Compression Compression is to be carried out as per batch manufacturing record. Collect the samples at various stages i.e. at start up, high RPM, low RPM, low weight at target speed, high weight at target speed, initial, middle and end of compression and carry out the testing of content uniformity and physical parameters such as hardness, thickness, friability etc.

Type of Flow of Powder Given in Table 5. Solubility Study The increase in solubility of Diclofenac sodium from pegylated dispersion was determined by following method. mg of core drug Diclofenac sodium was taken in 100 ml of phosphate buffer pH. 6.8 5 mg equivalent of pegylated preparation was also put it in 100 ml phosphate buffer pH 6.8. Both the solutions were sonicated, until dissolved. Both the solutions were filtered.They were diluted upto 20 to 25 times or as require. Absorbance was measured at λ max 254 nm. The increase in absorbance shows the increase insolubility.

Weight Variation Twenty tablets were randomly selected from each batch and individually weighed. The average weight and standard deviation of 20 tablets was calculated. The batch passes the test for weight variation test if not more than two of the individual tablet weight deviate from the average weight by more than the percentage described in official book.

VALIDATION OF SOLID DISPERSION TABLET [17, 22] The critical parameters considered during the process validation of Diclofenac sodium solid dispersion 20 tablets were: x Dry Mixing x Drying


Blending Compression Weight variation Thickness and Hardness Test Friability Assay Dissolution Study Disintegration Study

Thickness and Hardness Twenty tablets were randomly selected from each batch and there thickness and diameter was measured by using digital Vernier caliper. The crushing strength Kg/cm2 of

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RESEARCH ARTICLE Given in Table 10.

prepared tablets was determined for 10 tablets of each batch by using Monsanto tablet hardness tester. The average hardness and standard deviation was determined.

Thickness of the Solid Dispersion Tablet Given in Table 11.

Friability Twenty tablets were weighed and placed in the Electro lab friabilator and apparatus was rotated at 25 rpm for 4 minutes. After revolutions the tablets were deducted and weighed again percentage friability was measured using the formula

Assay of Solid Dispersion Tablet Given in Table 12. Disintegration of Solid Dispersion Tablet Given in Table 13.

% F = {1-(Wt/W)} ×100 Where, % F = friability in percentage, W = Initial weight of tablet, Wt = weight of tablets after revolution.

Dissolution of Solid Dispersion Tablet (For batch no: 1) Given in Table 14. Dissolution of Solid Dispersion Tablet (For batch no: 2) Given in Table 15.

Assay Triturate one tablet &weigh powder equivalent to 30 mg of diclofenac sodium & dissolve in 100 ml phosphate buffer 6.8 and dilute further to produce 30 μg/ml solution. Measure the absorbance of that solution at 254 nm and then find out the drug content using calibration curve.

Over all Summary of the Solid Dispersion Tablet Given in Table 16. RESULT AND DISCUSSION Flow Properties of Granules Flow properties of granules is given in Table 6.

Dissolution Study In Vitro dissolution study was carried out using USP II apparatus (Paddle apparatus) in 900 ml of phosphate buffer having pH 6.8 for 2.5 hr. The temperature of the dissolution medium was kept at 37± 0.5°C and the basket was set at 50 rpm. 10 ml of sample solution was withdrawn at specified interval of time (30 min) and filtered through Whattman filter paper from filtrate withdraw 1 ml solution and dilute upto 10 ml. The absorbance of the withdrawn samples was measured at λmax 254 nm using UV visible spectrophotometer. The concentration was determined from the standard curve of Diclofenac sodium dispersion tablet prepared in phosphate buffer having pH 6.8 at λ max 254 nm. Cumulative percentage of drug release was calculated using the equation obtained from a standard curve.

Weight Variation of solid dispersion tablet Weight variation of bilayer tablet is given in Table 7. Friability Test for solid dispersion tablet Friability Test for Bilayer Tablet is given in Table 8. Hardness Test Hardness test is given in Table 9. Diameter of the solid dispersion tablet Diameter of the solid dispersion tablet is given in table 10. Thickness of the solid dispersion tablet Thickness of the solid dispersion tablet is given in table 11.

In-vitro Disintegration The test was carried out using 6 tablets using Tablet disintegration tester ED-20 (Electro lab, Mumbai, India) distilled water at 37°C ± 2°C was used as a disintegration media and the time in second taken for complete disintegration of the tablet with no palable mass remaining in the apparatus was measured in seconds.

Assay of the solid Dispersion Tablet Assay of the solid dispersion Tablet is given in table 12. Disintegration Test Disintegration test is given in Table 13. Dissolution test Dissolution test is given in Table 14.

Flow Property of Granules Given in Table 6.

Overall Summary of the Solid Dispersion Tablet Given table 16.

Weight Variation of Solid Dispersion Tablet Given in Table 7.

CONCLUSION The aim of the present study was to develop an optimized formula for solid dispersion tablet containing Diclofenac sodium. Diclofenac sodium was planned to design to increase bioavailability and dissolution profile as a immediate release. The compressed solid dispersion tablets were also evaluated for weight variation, dimension, hardness, friability, drug content,

Friability of Solid Dispersion Tablet Given in Table 8. Hardness Test Given in Table 9. Diameter of the Solid Dispersion Tablet


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RESEARCH ARTICLE 11. Fee C J, Veronese F M. Protein conjugates purification and characterization, PEGylated Protein Drugs: Basic Science and Clinical Applications, Ed. Birkhauser Publishing: Basel, 113125, 2009. 12. Basic Principles of Validation by K Kiran & K Kathiresan. edit: 1, 35 – 36, 2005. 13. Handbook of Pharmaceutical Manufacturing Formulations by sarfaraj niazi edi: 4, 32 – 34. 14. Pharmaceutical Master Validation by Syed Imtiaz Haider, edit: 5, 14 – 23. 15. Pharmaceutical process validation by Nash and Berry, edit: 3, 432 – 434. 16. Review of pharmaceutical, (cited at 20th september) htmlhttp://goliath.ecnext.com/coms2/gi_0198-129995/Aliterature 17. Review of various pharmaceutical formulation, (cited at 10 september) http://www.accessdata.fda.gov/scripts/cdrh/ cfdocs/ cfcfr/CFRSearch.cfm?CFR Part=210 & show FR=1. 18. Pharmaceutical process validation, (cited at 26 september) http://www.asian guidelines.com 19. Safety Evaluation of pharmaceutical and medical device, New Pharmaceutical innovation, (cited at 15 september) http://www.fda.gov/cder/whatsnew.html. 20. Ainley D E, Paul J W. Hand book of pharmaceutical excipients, 2nd, 71, 215,355, 533. 21. Brahmankar D M, Jaiswal S B. Biopharmaceutics and Pharmacokinetics, Vallabh Prakashan, 1st Edn., 347-352, 1995. 22. Colombo P R, Bettini Manima. Journal of Parma Science, 8; 86, 1992-1993.

disintegration time & invitro drug release, complies with IP standard. So formulation was considered optimised formulation for fast & BABE release of diclofenac sodium. REFERENCES AND NOTES 1. Dau K, Sharma V K. Solid dispersion technology. Pharmabizj;, 10, 1-2, 2009. 2. Robert C J, Armas H N, Janssen S. Characterization of ternary solid dispersion of intraconazole PEG 6000. J Pharm sci., 97: 2110-2120, 2008. 3. Chiou W L, Rielman S. Pharmaceutical application of solid dispersion system. J Pharm.sci, 78: 10-12, 1971. 4. Horter D, Dressman J B. Physiochemical properties on dissolution of drug in the gastrointestinal tract. Adv Drug Del Rev, 25: 3-14, 1997. 5. Reagent and solution, In: Govt of India, Ministry of Health and Family welfare, Indian Pharmacopoeia, Controller of publication, New-Delhi, 2: 145, 1996. 6. Diclofenac sodium, In: Govt of India, Ministry of Health and Family welfare, Indian Pharmacopoeia, Controller of publication, New-Delhi, 1: 242, 1996. 7. Abuchowski A, McCoy J R, Palczuk N C, van Es T, Davis F F. Effect of covalent attachment of polyethylene glycol on immunogenicity and circulating life of bovine liver catalase, Journal of Biological Chemistry, 252(11), 3582–3586, 1977. 8. Veronese F M, Pasut G, PEGylation, successful approach to drug delivery, Drug Discovery Today, 10(21), 1451–1458, 2005. 9. Veronese F M, Harris J M. Introduction and overview of peptide and protein pegylation, Advanced Drug Delivery Reviews, 54(4): 453–456, 2002. 10. Fee C J, Van Alstine J M. PEG-proteins, Reaction engineering and separation issues, Chemical Engineering Science, 61(3): 924–939, 2006.


Cite this article as: Nirav S Kansagra, Vidhi N Kalola, Smita V Soriya, et al. Process Validation and Evaluation of Pegylated Solid Dispersion of Diclofenac Tablet. Inventi Rapid: Pharm Tech, 2013(1): 1-9, 2012.

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