INTRODUCTION:

Semi-solid dosage forms are normally presented in the form of creams, gels, ointments, or pastes. They contain one or more active ingredients dissolved or uniformly dispersed in a suitable base and any suitable excipients such as emulsifiers, viscosity-increasing agents, antimicrobial agents, antioxidants, or stabilizing agents.

The choice of a base for semi-solid dosage forms depends on many factors: the therapeutic effect desired the nature of the active ingredient to be incorporated, the availability of the active ingredient at the site of action, the shelf-life of the finished product, and the environmental conditions in which the product is intended to be administered.

Types of topical semi-solid dosage forms:

Cream:

Creams are homogeneous, semi-solid preparations consisting of opaque emulsion systems. Their consistency and rheological properties depend on the type of emulsion, either water-in-oil (w/o) or oil-in-water (o/w) and on the nature of the solids in the internal phase.

Types of Cream:

1. Hydrophobic creams (w/o):

Hydrophobic creams are usually anhydrous and absorb only small amounts of water. They contain w/o emulsifying agents such as wool fat, sorbitan esters, and monoglycerides.

2. Hydrophilic creams (o/w):

Hydrophilic creams contain bases that are miscible with water. They also contain o/w emulsifying agents such as sodium or triethanolamine soaps, sulfated fatty alcohols, and polysorbates combined, if necessary, with w/o emulsifying agents. These creams are essentially miscible with skin secretions.

GEL:

Gels are usually homogeneous, clear, semi-solid preparations consisting of a liquid phase within a three-dimensional polymeric matrix with physical or sometimes chemical cross-linkage by means of suitable gelling agents.

Classification of Gels:

Gels can be classified based on

ü Colloidal phases,

ü Nature of solvent

ü Physical nature

(a) Elastic gels

(b) Rigid gels

ü Rheological properties

(a) Pseudo-plastic gels

(b) Plastic gels

Preparation of Gels:

Gels can be prepared by following methods.

1. Thermal changes

2. Flocculation

3. Chemical reaction Loveleen Preet Kaur

Ointments:

An ointment is a homogeneous, viscous, semi-solid preparation, most commonly greasy, thick oil (oil 80% - water 20%) with a high viscosity that is intended for external application to the skin or mucous membranes

The different types of ointment bases are:

· Hydrocarbon bases, e.g. hard paraffin, soft paraffin, microcrystalline wax and ceresine

· Absorption bases, e.g. wool fat, beeswax

· Water-soluble bases, e.g. macrogols 200, 300, 400

· Emulsifying bases, e.g. emulsifying wax, cetrimide

· Vegetable oils, e.g. olive oil, coconut oil, sesame oil, almond oil and peanut oil.

Methods of preparation of ointments:

· Trituration:

In this finely subdivided insoluble medicaments are evenly distributed by grinding with a small amount of the base followed by dilution with gradually increasing amounts of the base.

· Fusion:

In this method the ingredients are melted together in descending order of their melting points and stirred to ensure homogeneity

EXPERIMENTAL WORK:

PREFORMULATION STUDIES:

Drug characterization- Diclofenac sodium:

Drug authentication:

Preformulation studies were performed to determine the physicochemical properties of drug that could affect the development and efficiency of new drug formulations.

1) Description:

The sample of drug was visually observed for the colour, odour and appearance .

2) Melting point determination:

Melting point of Diclofenac Sodium was determined by thiele’s tube method i. e. by taking a small amount of drug in one end closed capillary tube placed in melting point apparatus and the temperature at which the drug melts was noted. Average of triplicate readings was noted and compared with the literature.

3) Solubility study:

Excess amount of Diclofenac Sodium was added to 15 ml of dissolution medium in a 25 ml beaker maintained at 37 ± 0.5 ⁰C in a constant temperature water bath for 2h. At appropriate times i.e. 5,10,15,30,45,60,75 min; aliquots of 1ml were taken from the dissolution medium , filtered and then diluted to 100 ml. Calibration curves were used for the determination of the amounts dissolved.

4) Spectroscopic studies:

UV Spectroscopy:

Selection of sampling wavelength for analysis:

Preparation of standard stock solution:

Pure Diclofenac Sodium powder equivalent to 100 mg was accurately weighted and dissolved in 40 ml of 0.1 N HCL in a 100 ml volumetric flask and the volume was made up to the mark with 0.1 N HCL to obtain final concentration of 1000 μg/ml ( stock ‘A’ solution ). From the above stock ‘A’ solution 10 ml of aliquot was pipette out in a 100 ml volumetric flask and the volume was made up to mark with 0.1 N HCL to obtain the final concentration of 100 μg/ml ( stock ‘ B ’ solution ) .

5) Selection of analytical wavelength :

From the standard stock solution ‘B’ varlious of dilutions ranging between 1-20 μg/ml were prepared and scanned in the wavelength range of 400-200 nm using UV Spectrophotometer.

6) Preparation of Calibration curve for Diclofenac Sodium in Methanol:

Appropriate aliquots were pipetted out from the standard stock ‘B’ solution into a series 10ml volumetric flask. The volume was made up of the mark with methanol to get a set of solutions having the concentration range of 2,4,6,8,10,12,14,16,18 and 20 μg/ml for Diclofenac Sodium . Absorbance of the above solutions were measured at 231 nm and a calibration curve of absorbance against concentration was plotted the drug obeys Beer’s law.

Preparation of Calibration curve for Diclofenac Sodium in Phosphate Buffer pH 6.8:

The Preparation of the standard stock solution ‘ A’ and ‘ B ’ remains same as above from the standard stock solution ‘ B ’ various dilution ranging between 1-20 μg/ml were prepared and scanned in the wavelength range of 400-200 nm using Spectrophotometer having the concentration range of 2,4,6,8,10,12,14,16,18, and 20 μg/ml . Absorbance of the above solution was measured at 231 nm and a calibration curve of absorbance against concentration was plotted.

7) FTIR spectroscopy:

Identification of drug:

Diclofenac Sodium was subjected to FTIR spectroscopy. FTIR measurement of the drug was obtained on FTIR Jasco-410 .Sample was prepared by mixing with KBr (2mg sample in 200 mg KBr) and placing in the sample holder. The spectra were scanned over the wave number range of 4000-400 cm^{-1 at} the ambient temperature. Infrared spectroscopy is one of the most powerful analytical techniques which offer the possibility of chemical identification. This technique when coupled with intensity measurements may be used for quantitative analysis. One of the most important advantages of IR over the other usual methods of structural analysis is that it provides useful information about the structure of molecule quickly without tiresome evaluation methods. The technique is based upon the simple fact that a chemical substance shows marked selective absorption in the IR region. After absorption of IR radiation the molecules of chemical substance vibrates at many rates of vibration, giving rise to close packed absorption bands, called IR absorption spectrum which may extend over wide wavelength range. Various bands will be present in IR spectrum which will correspond to the characteristic functional groups and bonds present in a chemical substance. Thus, an IR spectrum of a chemical substance is a fingerprint for its identification. The infrared absorption spectrum of pure Diclofenac Sodium, and its physical mixture with polymer was recorded on FT-IR spectrophotometer. Diclofenac Sodium was subjected to FTIR spectroscopy.

Formulation of gel, cream and ointment:

Table no.1: Composition of Gel of Diclofenac Sodium

Sr. No	Ingredients	F1	F2	F3
1	Diclofenac sodium(gm)	1	1	1
2	Carbopol 940(gm)	0.4	0.6	0.8
3	Triethanolamine(ml)	0.2	0.2	0.2
4	Methyl paraben(gm)	0.18	0.18	0.18
5	Propyl paraben(gm)	0.02	0.02	0.02
6	Distilled water(gm)	100	100	100

Table no.2: Composition of Cream of Diclofenac Sodium

Sr. no	Ingredients(gm)	F1	F2	F3
1	Diclofenac sodium	1	1	1
2	Stearic acid	1	2	3
3	Glycerin	0.2	0.4	0.6
4	Lanolin	0.1	0.2	0.3
5	Triethanolamine	0.04	0.04	0.04
6	Methyl paraben	0.036	0.036	0.036
7	Propyl paraben	0.004	0.004	0.004
8	perfume	q.s.	q.s.	q.s.
9	Water(q.s.)	17.62	16.32	15.04

Table no.3: Composition of ointment of Diclofenac Sodium

Sr. no	Ingredients(gm)	F1	F2	F3
1	Diclofenac Sodium	1	1	1
2	Wool fat	0.2	0.3	0.4
3	Cetostearyl alcohol	0.3	0.2	0.4
4	Hard paraffin	0.4	0.2	0.3
5	White soft paraffin	18.1	18.3	17.9

Method of preparation:

v Preparation of Diclofenc Sodium Gel using Carbopol 940:

Carbopol 940 (1, 2, 3, 4, 5% w/w) and purified water were taken in a beaker and allowed to soak for 24 h. To this required amount of drug (2 gm) was dispersed in water and then Carbopol 940 was then neutralized with sufficient quantity of Triethanolamine. Glycerin as moistening agent, methyl paraben and Propyl paraben as preservatives were added slowly with contineous gently stirring until the homogenous gel was formed.

v Preparation of Diclofenac Sodium Cream:

1) Melt stearic acid and lanolin at 60^{0 c}.

2) Mix water, glycerin and triethanolamine and warm up to 60⁰c into second beaker.

3) Mix the two with continuous stirring.

4) Add the preservatives and perfumes.

5) Mix then thoroughly in order to obtain a uniform product.

v Preparation of Diclofenac Sodium Ointment:

1) Grate hard and weigh accurately all the ingredients.

2) Place them to melt in an evaporating dish on a water bath.

3) Stir gently to aid melting and to mix the ingredients.

4) When homogeneous, remove from the water bath and stir until cold.

5) Transfer to a container and cool it to obtain uniform product.

Evaluation of gel, Cream, Ointment:

1) Physical Characterization :

Inspect visually for colour, odour, and appearance

2) pH Determination:

By using pH meter 1 gm of formulation was stirred in distilled water to get a uniform dispersion. Volume was made to 100 ml. The electrode was immersed in formulation, distilled water and reading was recorded on pH meter.

3) Drug Content:

Each formulation (1 gm) was taken in a 100 ml volumetric flask .diluted with ethanol and shaken to dissolve the drug in it. The solution was filtered through what man filter paper no. 42. The content of the drug was estimated spectrophotometrically by using standard curve.

4) Determination of Spraedability:

Spraedability of the formulation was determined by the apparatus which consists of wooden block, which was provided by a pulley at one end. By this method spraedability was measured on the basis of slip and drug characteristics of formulation. An excess of sample (about 2 g) under study was placed on this glass slide. The sample was then sandwiched between this slide and another glass slide having the dimension of fixed ground slide and provided with the hook.1 gm weighted was placed on the top of the two slides for 5 minutes to expel air and to provide a uniform film of the between the slides. Excess of the drug sample was scrapped off from the edges. The top plate was then subjected to pull of 80 gm. With the help of string attached to the hook and the time (in seconds) required by the top slide to cover a distance of 7.5 cm to be noted. A shorter interval indicates better spraedability. Spraedability was calculated by using the formula:

S = M*L/T

Where,

S = Spraedability,

M = Weight in the Pan (Tied In the Upper Slide)

L = Length Moved By the Glass Slide

T = Time (In Sec) Taken To Separate The Slide Completely Each Other.

5) Determination of Extrudability:

Extrudability was determined by filling the sample in clean, lacquered aluminum collapsible tube and pressed firmly at the crimped end. When the cap was removed, sample extruded until pressure dissipated. Weight in grams required to extrude 0.5 cm ribbon of sample in 10 sec was determined.

6) Determination of Viscosity:

Viscosity of the formulation was determined by Brookfield viscometer. The viscosity measurements were done using Brookfield DV-11+ viscometer using LV-4 spindle. The developed formulation was poured into adaptor of the viscometer and determined the viscosity of the test sample as per standard operating procedure of viscometer. The spindle was rotated at speeds 0.5, 1, 5, 10 and 20 rpm.

7) In-vitro Diffusion Studies:

The diffusion studies were performed using Franz diffusion cell. The cell was locally fabricated and had a 25 ml receptor compartment. The cellophane membrane was mounted between a donor and receptor compartments. The formulation was applied uniformly on cellophane membrane and the compartments were clamped together. The receptor compartment was filled with phosphate buffer (pH 7.4) and the hydrodynamics of the receptor compartment were maintained by string with a magnetic bead. The study was carried out for 24 hrs with the interval of 0.5,1,2,4,6,8,10,12 and 24 hrs.5 ml sample was withdrawn from receptor compartment at predetermined time intervals and an equal volume of buffer was replaced. The samples were analyzed after appropriate dilution for drug content spectrophotometrically at 280 nm.

RESULTS AND DISCUSSION:

PREFORMULATION STUDIES:

Drug Characterization – Diclofenac sodium

A. Description:

The sample of Diclofenac was found to

Color: white

Odor: odorless

Taste: tasteless

State: fine crystalline powder

B. Melting Point Determination:

Melting point of Diclofenac was found to be 283-285 °C.

C. Solubility Study:

Insoluble in Water, Soluble in Acetone, 0.1 N HCl.

D. Spectroscopic Studies:

UV Spectroscopy:

Selection of sampling wavelength for analysis:

All the dilutions showed maximum absorbance at 231 nm for Diclofenac Sodium. Hence 231 nm was selected as the working analytical wavelength for UV calibration spectroscopy.

Figure 5: IR spectra ofCarbopol 940

B. IR spectra of Carbopol 940 + Diclofenac sodium

Figure 6: IR spectra of Carbopol 940 + Diclofenac sodium

Table no. 7: Interpretation of IR spectra of Carbopol 940

Peak	Value	Functional Group
1	1730.8	Ester
2	1240.97	C-H stretch
3	1149.37	C-N stretch
4	1020.96	C-O-C

Table no 8. Interpretation of IR spectra of Carbopol 940 + Diclofenac sodium

Peak	Value	Functional group
1	2951.52	C-H stretching
2	1730.08	Ester
3	1240.17	C-N stretching
4	1017.27	C-O stretching
5	988.33	Aromatic C-H
6	805.135	C-Cl stretching

Characterization of Gel, Cream and Ointment:

1. Evaluation of Diclofenac Sodium Gel

Formulation code	Clarity	Spreadability (g.cm/sec)	Extrudability	pH	Viscosity (cps)	Drug Content (%)
F1	+	18.75	+	5.7	3,20,000	97.21
F2	++	19.85	++	5.9	2,40,000	98.53
F3	+++	22.55	+++	6.1	1,92,000	99.92

Table 9. Determination of drug release

Sr no	Time in hours	% of drug release
1	1	51.40
2	2	63.56
3	3	69.01
4	4	75.20
5	5	89.26

2. Evaluation of Diclofenac Sodium Ointment

Formulation code	pH	Viscosity (cps)	Spreadability (g.cm/sec)	Extrudability	% drug release	Drug content (%)
F1	6.3	29,840	28.49	Easily extrudable	72.38%	76.1
F2	6.2	32,646	36.31	Easily extrudable	75.10%	81.2
F3	7.1	33,284	39.54	Easily extrudable	79.72%	86.7

Table 10: Physical Appearance

Sr no	Formulation code	Color	Homogeneity	Consistency
1	F1	White	Good	++
2	F2	White	Excellent	+++
3	F3	white	Excellent	+++

3. Evaluation of Diclofenac Sodium cream

Formulation code	pH	Spraedability (g.cm/sec)	Extrudability	Viscosity (cps)
F1	6.7	12.78	180	6710
F2	6.8	14.12	180	3147
F3	6.7	15	185	1614

Table 11: Determination of Drug release

Sr no	Time (hours)	% of drug release
1	1	34.98
2	2	43.03
3	3	51.17
4	4	66.82
5	5	74.45
6	6	84.19

CONCLUSION:

When semisolid preparations of drugs are used for the external application to the skin, the choice of suitable base plays an important role in delivering the drug to the skin. We have formulated different types of dermatological semisolids incorporating 1% Diclofenac sodium in each. The preparations include ointments, creams and gel. It has been concluded that the gel formulation showed better release compared to other ointment and cream formulations .It has been observed that carbopol 940 base also play a significant role in enhancing the release of drug, which could be due to their ability in solubilising Diclofenac sodium. Anhydrous & oleaginous bases showed poor release. Permeation enhancers can be used for enhance further release of drug from gel base. It was observed that Carbopol 940 gel containing Diclofenac sodium (F3) produced better spread ability and consistency as compared to other formulations. The developed F3 gel showed good viscosity, suitable pH, spread ability extrudability and good stability. The maximum percentage of drug release was found to be 98.68% in 6 hours in formulation F3. For topical ointments selection of right base plays an important role in delivering the drug to the skin. Among these formulations, formulation F3 showed high percentage of drug release i.e. 79.72% in 6 hours. The ointment formulations were excellent in homogeneity and consistency and white in color. The pH, viscosity, spread ability and extrudability of the formulations were found within the limit. From the above observations it was concluded that the formulation F3 showed high percentage of drug release. The percentage drug release for the cream formulation was found to be 84.19% in 6 hours. Physical evaluation including the determination of pH, spread ability, tube extrudability and viscosity was carried out on the cream at the time of preparation which was found within the limit. From the above observations it was concluded that the formulation F3 gives better drug release. From the above observations it was concluded that carbopol 940 gel base gives better drug release.

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Received on 14.07.2016 Accepted on 28.09.2016

Research J. Topical and Cosmetic Sci. 2016; 7(2): 46-54.

DOI: 10.5958/2321-5844.2016.00008.X

Concentration ( μg / ml )	Absorbance
0	0
2	0.339
4	0.595
6	1.104
8	1.546
10	1.90

Equation	Y= 0.194x-0.059
Slope	0.194
Intercept	0.059
R²	0.991

Concentration ( μg / ml )	Absorbance
0	0
2	0.154
4	0.375
6	0.546
8	0.712
10	0.910

Equation	Y=0.091x-0.007
Slope	0.091
Intercept	0.007
R²	0.998

Peak	Value	Functional Group
1	2922.59	Na Stretching
2	1090.55	C-N stretching
3	902.523	C-H stretching
4	804.171	Aromatic Ring