Design, Development and In-Vitro Characterization of Rapidly Disintegrating Oral Solid Dosage Form

Oral drug delivery is the most preferred and widely used route of administration due to its convenience, patient compliance, and cost-effectiveness. However, conventional solid dosage forms such as tablets and capsules may present challenges for certain patient populations, including paediatric, geriatric, and dysphagic patients, who often experience difficulty in swallowing. To overcome these limitations, rapidly disintegrating oral films (RDOFs) have emerged as a novel drug delivery system that offers a promising alternative to traditional dosage forms. Oral films are thin, flexible strips that dissolve or disintegrate rapidly when placed on the tongue, without the need for water. They ensure rapid onset of action by enabling drug absorption through the oral mucosa, bypassing first-pass metabolism. This is particularly advantageous for drugs requiring immediate therapeutic action, such as analgesics. Ketorolac Tromethamine, a non-steroidal anti-inflammatory drug (NSAID), is widely used for the short-term management of moderate to severe pain. It possesses a rapid onset of action, making it an ideal candidate for incorporation into oral films for fast relief. However, its bitter taste and need for rapid absorption necessitate the use of appropriate polymers and excipients to ensure patient acceptability and efficient drug delivery.

2. Aim, Objectives and Need of Study

Aim:   Design, Development and In Vitro Characterization of Rapidly Disintegrating Oral Solid Dosage form

Objective:

1. To formulate various batches of rapidly disintegrating oral solid dosage form by using various carrier alone and combination.
2. To improve the bioavailability and effectiveness of drug therapy by enhancing the disintegration rate and time of dosage form.
3. To improve the oral bioavailability of selected drug
4. To get the rapid onset of action
5. To improve patient compliances

3.  Drug Profile

Ketorolac tromethamine

Fig. 1. Chemical structure of ketorolac tromethamine

• Molecular Formula:  C19H24N2O6
• Molecular Weight:  376.41

• Solubility: soluble in water, ethanol, methanol, 
• Melting point:  160-165
• Uses:

 ? Pain Management (Analgesia)

• Moderate to severe acute pain: Commonly used after surgeries or injuries.
• Postoperative pain: Frequently administered after dental, orthopedic, or abdominal surgery.
• Renal colic: Effective in relieving pain caused by kidney stones.
• Musculoskeletal pain: Strains, sprains, or back pain.

? Anti-inflammatory Use

• Reduces inflammation in conditions like arthritis, though it’s not usually used long-term due to side effects.

? Ophthalmic Use (Eye Drops)

• Post-operative inflammation: After cataract or other eye surgeries.
• Seasonal allergic conjunctivitis: Helps relieve eye itching and inflammation.
• Corneal pain: From corneal refractive surgery or injury.

? Migraine Treatment (Off-label use)

• Sometimes used as an injectable alternative to relieve severe migraine headaches

4. Excipient Profile
   1. HPMC E5 (Hydroxypropyl Methylcellulose E5)

• Chemical Name: Hypromellose
• Synonyms: HPMC, Methocel, E464
• Molecular Formula: Variable (polymer), approximate repeating unit: C3H7O
• Molecular Weight: ~59.08 g/mol (monomer unit), full polymer MW varies (10,000–1,000,000 g/mol)
• Melting Point: 225–230°C
• Uses: Film former, binder, thickener, controlled-release agent
• Solubility: Soluble in cold water; insoluble in hot water and organic solvents

4.2. Crospovidone

• Chemical Name: Cross-linked polyvinylpyrrolidone
• Synonyms: Polyplasdone, Kollidon CL
• Molecular Formula: (C6H9NO)n
• Molecular Weight: Very high (crosslinked polymer; not defined)
• Melting Point: Does not melt (crosslinked polymer); decomposes above 150°C
• Uses: Super disintegrant in tablets and films
• Solubility: Insoluble in water but swells rapidly

4.3. SSG (Sodium Starch Glycolate)

• Chemical Name: Sodium carboxymethyl starch
• Synonyms: Explotab, Primojel
• Molecular Formula: (C6H10O5)nNa
• Molecular Weight: High (polymer)
• Melting Point: Decomposes on heating; does not have a defined melting point
• Uses: Superdisintegrant
• Solubility: Insoluble, but swells extensively in water

4 4. PEG 400 (Polyethylene Glycol 400)

• Chemical Name: Polyethylene glycol
• Synonyms: PEG-400
• Molecular Formula: H(OCH2CH2)nOH (n ≈ 8–9 for PEG 400)
• Molecular Weight: ~380–420 g/mol
• Melting Point: Liquid at room temperature
• Uses: Plasticizer, solvent, humectant
• Solubility: Freely soluble in water and alcohol

4. 5. Croscarmellose Sodium

• Chemical Name: Cross-linked sodium carboxymethyl cellulose
• Synonyms: Ac-Di-Sol
• Molecular Formula: Variable (cellulose derivative with sodium carboxymethyl substitution)
• Molecular Weight: High (polymeric)
• Melting Point: Decomposes on heating
• Uses: Super disintegrant
• Solubility: Insoluble but swells in water

4.6. Pullulan

• Chemical Name: α-1,6-Maltotriose polysaccharide
• Synonyms: Pullulan polysaccharide
• Molecular Formula: (C18H30O15)n
• Molecular Weight: ~200,000 Da
• Melting Point: >100°C (decomposes)
• Uses: Film-forming agent in oral films and capsules
• Solubility: Freely soluble in hot and cold water

4.7. Saccharin Sodium

• Chemical Name: Sodium o-benzoic sulfimide
• Synonyms: Sodium saccharin, E954
• Molecular Formula: C7H4NO3SNa
• Molecular Weight: 205.17 g/mol
• Melting Point: 226–230°C (decomposes)
• Uses: Artificial sweetener, taste-masking agent
• Solubility: Freely soluble in water; slightly soluble in alcohol

5.MATERIAL AND METHOD

5.1. Preformulation Studies:

Preformulation studies are the first step in rational development of dosage form of a drug substance Preformulation study is the process of optimizing the delivery of the drug through the determination of the physicochemical properties of the new compound that affect the drug performance and development of an efficacious, safe and stable dosage form. It gives the information needed to define the nature of the drug substance and provide a framework for the drug combination with the pharmaceutical excipients in the dosage form. Hence, these studies were performed for the obtained sample of drug for identification and compatibility studies.

5.2. Organoleptic Properties

1) Colour: A small quantity of Quetiapine fumarate powder was taken on a butter paper and was viewed in a well illuminated place.

2) Taste and Odour: Very less quantity of Quetiapine fumarate was tasted and smelled to get odour.

5.3. Standard Calibration curve of Ketorolac tromethamine:

Calibration curve of  Ketorolac tromethamine   was carried out in Phosphate buffer of pH 6.8 and absorbance was taken by using UV spectrophotometer Preparation of Phosphate buffer of pH 6.8.

• Preparation of 0.2 M sodium hydroxide:

Dissolve about  4 g of sodium hydroxide in sufficient quantity of distilled water and made up to 500ml with distilled water.

• Preparation of 0.2 M potassium dihydrogen phosphate:

Dissolve potassium phosphate about 13.609 g in sufficient quantity of distilled water and made up to 500ml with distilled.

• Preparation of Phosphate buffer of pH 6.8:

Mix 250ml of potassium dihydrogen phosphate and 112 ml of sodium hydroxide were mixed together and made up to the volume of 1000ml with distilled water.

• Calibration curve of Ketorolac tromethamine in pH 6.8:

100 mg of drug  Ketorolac tromethamine was dissolved and volume was make up to 100ml using phosphate buffer 6.8 to make stock solution of concentration 200µg/ml. Then 0.2 ml of stock solution was taken and diluted upto 100ml with the buffer of pH 6.8 and to get concentration of 2µg/ml and in similar way dilution were made as 2, 4, 6, 8 and 10 µg/ml respectively and absorbance measured at 322nm by UV visible spectrophotometer. The absorbance values were plotted against concentration (µg/ml) to obtain the standard calibration curve.

5.4. Formulation of drug loaded films

Drug  loaded films were also prepared by solvent casting method. The 180 mg of Ketorolac tromethamine  was incorporated into 2-2 cm area of film. Drug added into the Forming solution was calculated by considering total amount of solution to be poured in order to obtain films with desired thickness on a specific surface area of the petri plate Solution was then casted in to a Petri dish having area of 38.46cm and  Petri dish was kept in hot air oven for 12 hr at 50?C

Determination of dose of drug

The calculation of the dose depends upon the surface area of petri dish

The surface area of petri dish = 38.46cm * 2

The dose of diclofenac sodium 20 mg No of 4 cm2 ( 2 * 2) present in whole = 38.46cm =  9 films

 Amount of drug require -= 9 * dose

                                       =  9 * 20

                                       = 180 mg

The amount of drug added in each plate was approximately equal to 180 mg

5.5.Formulation development of oral film of  Ketorolac tromethamine⁷⁹ 

Casting process of fast disintegrating oral film

Various methods are available for casting of oral films. This is fast disintegrating oral film hence on the laboratory scale solvent casting technique was adopted for formulation of films.

• Solvent casting method

Drug Ketorolac tromethamine containing fast dissolving films where fabricated by the solvent casting method . the required amount of HPMCE5 and pullulan was dissolved in 5ml of distilled water on a magnetic stirred for 20 min.. In another beaker, take the 1 ml ethanol then add the drug , superdisintergrating agent, plasticizer, orange oil , PEG 400 and saccharine sodium and where mixed properly. Then add both the solution on magnetic stirred and placed it until air bubbles  removed the solution was poured into a petri dish and dried at room temp for 48 hr. then films was formed and  cut into required size (2*2) for testing. The films where stored in air tight plastic bages till further use.

Table No.1. Formulation Table of fast dissolving oral films of Ketorolac tromethamine

6.Evaluation of FDOFs⁷⁰

6.1 Physical characterizations of fast dissolving oral films:

• Thickness of films

The thickness of the film was measured by micro meter screw gauge at three different places and average of  three values was calculated. This is essential  to ascertain uniformity in the thickness of the film which is directly related to the accuracy of dose in the film.

• Weight of films / weight variation

Oral fast dissolving films were weighed on analytical balance and average weight can be determined for each film. It is desirable that films should have nearly constant weight. It is useful to ensure that a film contains the proper amount of excipients and API.

• Folding endurance

Folding endurance of the film is essential to study the elasticity of the film during storage and handling. The folding endurance of the film films was determined by repeatedly folding one film at the same place till it broke. This is considered to reveal good film properties. A film (2 X 2 cm) was cut evenly and repeatedly folded at the same place till it breaks. The number of times the  film could be folded at the same place without breaking  gave the exact  value of folding endurance. All determination were performed in triplicate

• pH value

The  pH  value  was  determined  by  dissolving  one  oral  film  in  10  ml  distilled  water  and measuring the pH of the obtained solution. All determinations were performed in triplicate. It is necessary that strip should have nearly uniform pH value

• In-vitro disintegration

Disintegrating time is defined as the time (sec) at which a film breaks when brought in contact with water or saliva. 6.Petri dish method Put 2ml of distilled water into a petri dish, add a film on the water surface, and measure the time for the oral film to completely dissolve.

• Percentage moisture loss

Percentage moisture loss was also carried to check the integrity of films at dry condition. It is determined by placing the prepared film in desiccators containing anhydrous calcium chloride. After three days, the film was taken and reweighed. The percent moisture loss was calculated using the following formula.

% Moisture loss Initial weight - Final weight/Initial weight x 100

• Folding Endurance

The folding endurance of the film was determined by repeatedly folding one film at the same place till it breaks from the one end of the film. The number of times of film could be folded at the same place without breaking was noted which gave the value of the folding endurance.

• Drug content uniformity

Three films (4cm²) of each were transferred in to separate graduated flasks containing 100 ml of phosphate buffer Ph 6.8 and continuously stirred for 2 hrs. the solutions were filtered, suitably diluted and analyzed at 276 nm and the drug content was calculated

• In vitro dissolution studies

The phosphate buffer pH 6.8 was taken as the dissolution medium to determine the drug release. The dissolution profile of quick release films of Diclofenac sodium was carried out using USP dissolution testing apparatus-1 (basket type) containing 900 ml of the phosphate buffer pH 6.8. The film was placed in the basket, maintained at 37 ± 0.5°C and the agitation speed was 50rpm. Aliquots (1 ml) of the dissolution medium were withdrawn at 1,2,4, 6, 8, and 10 minutes time intervals and the same amount was replaced with the fresh medium. Samples were assayed spectrophotometrically at 322 nm. The cumulative percentage drug release was calculated.

Table No 2- In-Vitro Dissolution Study

7.Physical Characteristics:    

Table No. 3:  Physical characteristics of Ketorolac Tromethamine

7.1.    Solubility study:

Table No. 4: Solubility Study

7.1.  Analytical Characterization of Drug Sample:

• Standard calibration Curve of Ketorolac Tromethamine:

100 mg of drug Ketorolac Tromethamine was dissolved in distilled water and volume was make up to 100ml with phosphate buffer 6.8. Then 0.2 ml of stock solution was taken and diluted upto 100ml with the buffer of pH 6.8 and to get concentration of 2µg/ml and in similar way dilution were made as 2, 4, 6, 8 and 10 µg/ml respectively and absorbance measured at 322 nm by UV visible spectrophotometer. The absorbance values were plotted against concentration (µg/ml) to obtain the standard calibration curve.

Table no 5: Calibration of Ketorolac Tromethamine in pH 6.8 Phosphate buffer

Figure No.1. Calibration Curve of Ketorolac Tromethamine with Ph 6.8 Phosphate Buffer

Correlation Coefficent (R²)=0.9989

 Equation of Regressed Line Y= 0.00436x-0.0045             Where , X=Value of Concetration

Y=Regressed value of Absorbance

7.2. Drug Interaction Studies (Compatibility Studie

FT-IR Spectroscopy

It's important to check any kind of interaction between drug candidate and polymer. The polymers which are to be incorporated into formulation should be compatible with the drug. This compatibility study or interaction study was done using Fourier Transformed Infrared Spectroscopy. IR Spectra of pure  ketorolac tromethamine and Polymer Viz. HPMC E5,Pullulan, saccharin sodium, PEG 400, SSG, croscarmellose sodium, crosprovidone were taken separately. Then to know if there is any interaction between and polymer, IR spectra of  ketorolac tromethamine and polymers were taken in combination. The results shows that there was seen between drug ketorolac and polymers as there was no significant change in the pattern of peaks of optimized batch of FDOFs  with pure drug.

Figure No 2. IR Spectra of Ketorolac (Pure Drug)

Table No. 6: IR Interpretation of ketorolac  (Pure Drug)

Figure 3. IR spectra of Polymer HPMC E5

Figure 4. IR spectra of Polymer pullulan

Figure 5. IR spectra of  optimized batch of drug , polymers and excipient

Table No. 7: IR Interpretation of  optimized batch of drug , polymers and excipient

Physical characteristics

The physical characterization of FDOFs was carried out by visual inception and the               following observation where made. all the formulation (films) where evenly coloured and no migration of colour was observed. The increased thickness of film is attributed to the increase in the amount of HPMC. Formulation F1 to F5 found to be brittle in nature. Formulation F3 was to soft and difficult to handle. And all batches was found to be smooth surface area and all formulations are non tacky.

Table No 8 :- Showing Physical Characteristics Of Fil

• Surface PH

Surface pH of all mouth dissolving films prepared by different polymers was found to be in the range of 6.7 to 9.6 pH, which was close to the neutral pH, which indicated that films may have less potential to irritate sublingual mucosa & hence, more acceptable by the patients

• Weight variation and thickness

A result showed that as the concentration of polymer increases weight of film also increases or decreases . The weight variation of the formulation was in the range of 50 to 150 mg, which was acceptable. Thickness of mouth dissolving film depends on conc of polymer, thickness of all mouth dissolving film was measured with digital vernier caliper showed thickness value in range of 0.21 to 0.29 mm.

• Folding Endurance

Folding endurance gives an indication of brittleness of the film. It was shown that as the concentration of polymer and plasticizer increases, folding Endurance of mouth dissolving film increases. The folding endurance value of the prepared films ranged from 86 to 112,  where the results are summarized. The optimized film (F5) has folding endurance value of 85±1, which was desirable.

• Drug content uniformity

 All the fast dissolving oral films were found to contain an almost uniform quantity of the drug, as per content uniformity studies indicating reproducibility of the technique. Drug content in the films was evaluated and the values were found to be between 85% to 115%. F4 batch was optimized on the basis high drug content (89.3%)

• In vitro disintegration studies.

The disintegrating time of all the formulations was ranges from 15 to 30 see the results were depicted. The disintegration time . of optimized formulation (F5) was found to be 23 sec which was very less and desirable for quick onset  of action.

• Percentage Moisture Loss

 Moisture loss in oral films is a critical parameter to ensure film stability and quality. Ideally, moisture loss should fall within the range of 2–6% for most formulations. Higher moisture loss (above 6%) may indicate over-drying or excessive hygroscopicity, which could affect shelf life and handling. All formulation batches shows the ideal rang . but F3 batch shows higher than ideal range.

Table No 13:- Showing Evaluation Of Ketorolac Films

• In vitro drug release studies

Cumulative % drug release was calculated on the basis of drug content of ketorolac present in the respective film. The results obtained in the in vitro drug release for the formulations were given. Formulation F1 to F5 shows drug release. 

Table No 14:- % Drug Release Of Formulation

The ultimate aim of this present work was to develop immediate release drug delivery system of ketorolac. The In vitro cumulative drug release profile of these formulations showed up to 95.28% release in 10 min the formulation F5 showed satisfactory drug release in 10 min i.e. 95.28% which is considered as an optimized batch. During the study concluded that the film were dissolves immediately and gives highest % drug release up to 10 min.

Fig No 15: - Cumulative % Drug Release of F1 To F5

The present study aimed to formulate and evaluate fast dissolving oral films (FDOFs) of Ketorolac Tromethamine, an NSAID, for immediate drug release and improved patient compliance, particularly for individuals with difficulty swallowing conventional dosage forms. Ketorolac Tromethamine was characterized by its white to off-white color, bitter taste, odourless nature, and a melting point ranging between 160–165°C. The drug demonstrated good solubility in solvents such as water, ethanol, methanol, DMF, acetone, and DMSO. Analytical evaluation was performed using UV-visible spectrophotometry at 322 nm, with the calibration curve showing excellent linearity (R² = 0.9989) based on the regression equation Y = 0.00436x - 0.0045. FT-IR compatibility studies confirmed no significant interactions between Ketorolac and selected polymers and excipients (HPMC E5, Pullulan, PEG 400, saccharin sodium, SSG, croscarmellose sodium, crospovidone), validating their suitability for formulation development. Five different formulations (F1–F5) were prepared and evaluated. All films exhibited smooth, transparent, and non-tacky surfaces with surface pH values ranging from 6.72 to 7.12, indicating minimal irritation potential to the oral mucosa. The weight variation across formulations was within the acceptable range of 50–150 mg, and film thickness varied between 0.21 to 0.29 mm. Folding endurance, an indicator of film brittleness, ranged from 80 to 91, with F5 showing a desirable value of 86. Drug content uniformity across films ranged from 23.58% to 89.3%, with F5 achieving the highest uniformity. Moisture loss in the films generally fell within the ideal 2 6% range, except for F3, which exceeded this threshold. The in vitro disintegration times of the films ranged from 15 to 36 seconds, with F5 disintegrating the fastest at 23 seconds. In vitro drug release studies revealed that formulation F5 released 95.28% of the drug within 10 minutes, indicating efficient and rapid drug delivery. Thus, formulation F5 was identified as the optimized batch, demonstrating excellent mechanical and pharmaceutical properties, confirming its potential as a fast-acting oral dosage form for Ketorolac Tromethamine.

CONCLUSION

The present study aimed to formulate and evaluate fast dissolving oral films (FDOFs) of Ketorolac Tromethamine, an NSAID, for immediate drug release and improved patient compliance, particularly for individuals with difficulty swallowing conventional dosage forms. Ketorolac Tromethamine was characterized by its white to off-white color, bitter taste, odourless nature, and a melting point ranging between 160–165°C. The drug demonstrated good solubility in solvents such as water, ethanol, methanol, DMF, acetone, and DMSO. Analytical evaluation was performed using UV-visible spectrophotometry at 322 nm, with the calibration curve showing excellent linearity (R² = 0.9989) based on the regression equation Y = 0.00436x - 0.0045. FT-IR compatibility studies confirmed no significant interactions between Ketorolac and selected polymers and excipients (HPMC E5, Pullulan, PEG 400, saccharin sodium, SSG, croscarmellose sodium, crospovidone), validating their suitability for formulation development. Five different formulations (F1–F5) were prepared and evaluated. All films exhibited smooth, transparent, and non-tacky surfaces with surface pH values ranging from 6.72 to 7.12, indicating minimal irritation potential to the oral mucosa. The weight variation across formulations was within the acceptable range of 50–150 mg, and film thickness varied between 0.21 to 0.29 mm. Folding endurance, an indicator of film brittleness, ranged from 80 to 91, with F5 showing a desirable value of 86. Drug content uniformity across films ranged from 23.58% to 89.3%, with F5 achieving the highest uniformity. Moisture loss in the films generally fell within the ideal 2 6% range, except for F3, which exceeded this threshold. The in vitro disintegration times of the films ranged from 15 to 36 seconds, with F5 disintegrating the fastest at 23 seconds. In vitro drug release studies revealed that formulation F5 released 95.28% of the drug within 10 minutes, indicating efficient and rapid drug delivery. Thus, formulation F5 was identified as the optimized batch, demonstrating excellent mechanical and pharmaceutical properties, confirming its potential as a fast-acting oral dosage form for Ketorolac Tromethamine. This dosage form offers significant advantages over conventional tablets, especially for pediatric, geriatric, and dysphagic patients, by eliminating the need for water during administration and enhancing patient compliance. Overall, oral fast dissolving films represent a viable and effective platform for delivering drugs like Ketorolac for immediate relief.

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8.4. Physical characteristics

The physical characterization of FDOFs was carried out by visual inception and the               following observation where made. all the formulation (films) where evenly coloured and no migration of colour was observed. The increased thickness of film is attributed to the increase in the amount of HPMC. Formulation F1 to F5 found to be brittle in nature. Formulation F3 was to soft and difficult to handle. And all batches was found to be smooth surface area and all formulations are non tacky.

Table No 12: - Showing Physical Characteristics of Films

• Surface PH

Surface pH of all mouth dissolving films prepared by different polymers was found to be in the range of 6.7 to 9.6 pH, which was close to the neutral pH, which indicated that films may have less potential to irritate sublingual mucosa & hence, more acceptable by the patients

• Weight variation and thickness

A result showed that as the concentration of polymer increases weight of film also increases or decreases . The weight variation of the formulation was in the range of 50 to 150 mg, which was acceptable. Thickness of mouth dissolving film depends on conc of polymer, thickness of all mouth dissolving film was measured with digital vernier caliper showed thickness value in range of 0.21 to 0.29 mm.

• Folding Endurance

Folding endurance gives an indication of brittleness of the film. It was shown that as the concentration of polymer and plasticizer increases, folding Endurance of mouth dissolving film increases. The folding endurance value of the prepared films ranged from 86 to 112,  where the results are summarized. The optimized film (F5) has folding endurance value of     85±1, which was desirable.

• Drug content uniformity

All the fast dissolving oral films were found to contain an almost uniform quantity of the drug, as per content uniformity studies indicating reproducibility of the technique. Drug content in the films was evaluated and the values were found to be between 85% to 115%. F4 batch was optimized on the basis high drug content (89.3%)

• In vitro disintegration studies.

The disintegrating time of all the formulations was ranges from 15 to 30 see the results were depicted. The disintegration time . of optimized formulation (F5) was found to be 23 sec which was very less and desirable for quick onset  of action.

• Percentage Moisture Loss

Moisture loss in oral films is a critical parameter to ensure film stability and quality. Ideally, moisture loss should fall within the range of 2–6% for most formulations. Higher moisture loss (above 6%) may indicate over-drying or excessive hygroscopicity, which could affect shelf life and handling. All formulation batches shows the ideal rang but F3 batch shows higher than ideal range.

Table No 13: - Showing Evaluation Of Ketorolac Films

In Vitro Drug Release Studies

Cumulative % drug release was calculated on the basis of drug content of ketorolac present in the

respective film. The results obtained in the in vitro drug release for the formulations were given. Formulation F1 to F5 shows drug release. 

DISCUSSION: -

The ultimate aim of this present work was to develop immediate release drug delivery system of ketorolac. The In vitro cumulative drug release profile of these formulations showed up to 95.28% release in 10 min the formulation F5 showed satisfactory drug release in 10 min i.e. 95.28% which is considered as an optimized batch. During the study concluded that the film were dissolves immediately and gaves highest % drug release up to 10 min.

Fig No 15: - Cumulative % Drug Release of F1 To F5