INTRODUCTION

A variety of pharmacological dosage forms has proven effective in alleviating both acute and chronic conditions in individuals. These formulations are well-known for their swift absorption of the active ingredient. Recent technological advances have likewise paved the way for innovative medication-delivery strategies^1-3.

By employing this technique, the delivery timing of the medication can be regulated. The term “controlled release” denotes delivery strategies that exert control over the rate and/or pattern of medication release inside the body. In other words, the system strives to maintain drug concentration locally within the target tissue or cell type. Consequently, continuous-release platforms deliver only a fleeting elevation of therapeutic blood or tissue concentrations. In this section, the difference between continuous and controlled release becomes evident^4,5.

The chief objective of investigating and devising innovative means of administering medication is to heighten drug delivery’s efficacy and safety while offering greater convenience to the patient. Extensive research conducted over the past several years has spawned technologies that fulfil the requirements for non-invasive medication delivery. Transdermal medicine administration, for instance, represents such a technology^6,7.

Methodology Followed:

Following the acquisition of various analytical-grade polymers and chemicals, together with the purchase of the pure ketoprofen drug, the steps outlined below were carried out in the present investigation.

Preformulation Studies:

A preformulation investigation aims to identify and verify a drug through its diverse physico-chemical characteristics. Such parameters are regarded as crucial in developing a dosage form that is stable, effective, and safe. The procedure involved measuring ketoprofen’s melting point and its solubility in selected aqueous and non-aqueous solvents at ambient temperature, as well as its partition coefficient between n-octanol and both water and phosphate buffer solutions^8,9.

The preformulation study further comprised the measurement of the absorbance maximum (λ max) and the construction of the standard calibration curve for API.

Determination of λ max:

One hundred milligrams of pure ketoprofen was dissolved in 100mL of pH 7.4 phosphate buffer, and 1 ml of the resulting solution was transferred into a separate 10ml volumetric flask, adjusted with suitable media, and analyzed via UV scanning from 200 to 400 nm on a double-beam UV–visible spectrophotometer.

Preparation of Calibration Curve:

A 1000μg/ml solution was prepared by dissolving 50mg of the medication in sufficient ethanol to reach 50ml of the dissolution medium (PBS at pH 7.4) inside a 50-ml volumetric flask, then subjecting the solution to sonication for 20 minutes in a bath sonicator. The solution thus obtained was labeled stock Solution-I. Adding 10ml of the stock solution into 100ml of the dissolving medium produced 100µg/ml solution. The solution obtained was labelled as standard stock solution-II.

Aliquots of 0.2ml to 2.0ml were transferred into succession of 10ml volumetric flasks to attain concentration series spanning 2–20µg/ml.

Subsequently, UV Spectrophotometer (UV-1800, Shimadzu, Japan) was employed to measure the absorbance of the obtain solutions at 260nm against the parent solvent as the blank. The plot of absorbance against concentration in µg/ml PBS of pH 7.4 produced the standard curves.

Drug-polymer interaction studies by FT-IR spectrophotometry:

The FT-IR spectrophotometer was utilized to capture the spectra of the drugs, polymers, and the optimized transdermal patches. Approximately ten to fifty mg of each sample was weighed out in a mortar and intermittently crushed with 100–150mg of potassium bromide until a pellet formed. The triturated samples were transferred to a holder and scanned in the range of 400–4000 cm-1.

Composition of Transdermal Patches:

Transdermal patches were fabricated through the solvent casting technique. To begin with, the mucilage was extracted from the flax seed. For this purpose, the seeds were weighed and immersed in room temperature distilled water overnight. Subsequently, the solution was strained, heated and, subsequently, cooled to yield the mucilage from the flax seeds.

In preparing the TD patches, requisite amounts of HPMC E15 (1g) and FM (1g) were weighed and combined in a 50ml solvent of distilled water: methanol (1:1 ratio). Stirred the mixture above a hot water bath until it had completely dissolved. Once the solution had cooled to 25^oC, the drug (Ketoprofen) 250mg was introduced. Subsequently, 0.5ml each of PEG 400 and glycerol were introduced. Likewise, identical procedures were carried out for HPMC E100.

In both situations the formulation was subsequently introduced into a glass Petri dish and left to air-dry at room temperature for 24hours. For one day, the Petri dish remained undisturbed at room temperature. The patch was carefully peeled off the petri dish in one piece, and the transdermal patches were then trimmed into rectangular strips measuring 2 × 4 cm. The patch was gathered and placed inside a desiccator for future utilization.

Table 1: Composition of various Ketoprofen transdermal patch formulations

Ingredients	F 1	F 2	F 3	F 4
HPMC E15 (mg)	-	10.5	-	20.5
HPMC E100 (mg)	-	-	20.5	-
FM	30	25	15	10
PEG 400	0.5 ml	0.5 ml	0.5 ml	0.5 ml
Glycerol	0.5 ml	0.5 ml	0.5 ml	0.5 ml
Methanol: Water (1:1)	50 ml	50 ml	50 ml	50 ml
Ketoprofen (mg)	250	250	250	250

In this context, incorporating glycerol into a flaxseed mucilage-containing transdermal patch may strengthen the film’s physical characteristics, facilitate drug delivery, and deliver additional benefits for the skin.

Evaluation of Ketoprofen Transdermal Patches:

The prepared ketoprofen-loaded patches were characterized for various physicochemical parameters, including their in vitro release profile and stability under varied conditions.

Overall visual look:

All the transdermal patches were visually scrutinized for color, clarity, flexibility, and smoothness.

Thickness:

Using a digital micrometer, the thickness of the drug-loaded polymeric films was assessed at five separate points. For each batch of the drug-loaded film, the average and standard deviation values were computed from the five recorded readings.

Folding Potential:

A 2 x 4cm patch was trimmed evenly and continuously folded at one designated spot until it fractured. The count of folds at the same site until the film broke determines its folding endurance value.

Consistency in Weight:

Before the testing, the films of each batch were dried at 60°C for 4h. A digital balance was used to weigh five patches from every batch with precision. From the patient weights, the mean and standard deviation were obtained. Each film’s weight should vary only minimally from the average weight of the films.

Moisture Content:

The film was weighed and placed in a desiccator containing anhydrous calcium chloride at 40°C in a dryer for 24h, after which it was reweighed periodically until a stable weight was achieved. Moisture content was calculated as the difference between the final weight remained constant and the film’s original weight.

Moisture Uptake:

A weighed film was sealed in a desiccator at 40°C for 24 h before its moisture uptake was assessed. In two distinct desiccators maintained at room temperature, the films were each subjected to distinct relative humidity of 75% RH and 93% RH using saturated solutions of sodium chloride and ammonium hydrogen phosphate, respectively. Moisture uptake was calculated as the difference between the constant final weight obtained and the initial weight.

In vitro diffusion Studies:

In vitro diffusion of the polymeric films was investigated using a modified Franz diffusion cell equipped with a Cellophane membrane. To serve as the elution medium, 15ml of a phosphate buffer adjusted to pH 7.4 was employed. The films under scrutiny were positioned between the donor and receptor compartments so that the drug-releasing surface pointed toward the receptor medium. Uniform distribution of the drug in the elution medium was secured by stirring with a magnetic bar at a speed of 60 rpm. Thermostatic regulations kept the whole apparatus at 37º±1ºC. A 1-ml aliquot was withdrawn at appropriate intervals, and the withdrawn volume was instantly replenished with an equal volume of fresh buffer. The quantity of drug diffused through the skin was evaluated using UV spectrophotometry. All the recorded data were subsequently tabulated, and various classical kinetic equations were employed to elucidate the diffusion cell’s kinetics and mechanism.

Stability Studies:

Stability of a drug is described as the capacity of a specific formulation package to maintain its physical, chemical, therapeutic, and toxicological characteristics over its entire shelf life. According to the ICH guidelines, accelerated stability evaluations were performed on the optimized batches of each drug’s film formulation. Stability testing aims to furnish evidence regarding the quality of a drug substance or its product, which changes over time when exposed to environmental factors such as temperature, humidity, and light. Appropriate storage conditions, retest intervals, and the corresponding shelf life must be set.

The chosen formulations were housed in amber bottles sealed with cotton and capped tightly with aluminium. Subsequently, the formulations were held at 25ºC / 60% RH, 30ºC / 65% RH, and 40ºC / 75% RH for six months, after which their drug content and permeation performance were assessed.

Skin Irritation test:

To assess the formulation’s sensitivity toward the skin, the prepared patches were applied to self-skin in the upper-arm area for 24 hours, and any associated skin inflammation effects were documented.

RESULTS AND DISCUSSION:

With respect to their physical characteristics, the prepared patches exhibited uniformity, smoothness, flexibility, and homogeneity. The determined melting point of 94.61±0.66 was consistent with the accepted range of 92–97°C for pure ketoprofen¹⁰.

Solubility study:

The solubility of ketoprofen in selected aqueous and non-aqueous media at room temperature is tabulated in Table 2.

Table 2: Solubility profile of Ketoprofen

S. No.	Solvent	Solubility
1.	Ethanol (95%)	1-10 parts
2.	Dichloromethane	30- 100 parts
3.	Acetone	30- 100 parts
4.	Methanol	10- 30 parts
5.	Trichloromethane	30- 100 parts
6.	Distilled Water	100- 1000 parts
7.	Phosphate buffer pH 7.4	10- 30 parts

Examining the data presented above, it is evident that ketoprofen dissolves readily in ethanol, and maintains sufficient solubility in methanol as well. As the results reveal, it has only moderate solubility in water and aqueous media. These findings concurred with earlier authenticated studies¹¹.

Partition coefficient:

In the n-octanol: water, n-octanol: PBS (pH 5.5), and n-octanol: PBS (pH 7.4) media, the partition coefficients measured were 2.723±0.126, 2.451±0.081, and 2.187± 0.119, respectively. These results indicate that the compound exhibits pronounced lipophilicity and, consequently, is suitable for creating a transdermal drug delivery system. In this context, the results agree with those reported earlier^11,12.

λ max and Calibration Curve:

λ max was determined to occur at 260 nm. The result was consistent with those recorded in earlier studies and coincided closely, thereby confirming the result obtained in the present investigation ^13,14.

The calibration plot prepared obeyed the Beer-Lambert law within the 2–20µg/ml concentration range. By recording the sample’s absorbance at 260nm and projecting it onto the standard plot, the concentration of drug contained in the sample was subsequently calculated (table 3 and figure 1).

Table 3: Ketoprofen Calibration data in PBS pH 7.4 at λ max 260nm

S. No.	Concentration (µg/ml)	Absorbance	Statistical Parameters
1.	2	0.164±0.015	R2= 0.9973 Y = 0.0269x + 0.0335
2.	4	0.184±0.018
3.	6	0.256±0.012
4.	8	0.281±0.015
5.	10	0.356±0.013
6.	12	0.397±0.013
7.	14	0.456±0.016
8.	16	0.487±0.012
9.	18	0.546±0.016
10.	20	0.615±0.015

Values are expressed as mean ± S.D., n=3

Figure 1: Ketoprofen Calibration curve in PBS with pH 7.4 at λ max 260 nm

A linear calibration profile was observed across the 20–200 ng/ml concentration range (Figure 1). The equation derived was y = 0.0269x + 0.0335 (R² = 0.997). The correlation coefficient reveals that the technique is linear (Table 3).

IR spectra of API Ketoprofen, individually and along with other polymers:

Clear peaks emerged in the IR spectrum of ketoprofen at 1655, 1598, and 1457 cm⁻¹—most likely stemming from C=C stretching within the benzyl ring. The principal peaks arise at 1697 cm⁻¹ from C=O stretching and at 1228 cm⁻¹ from C-O stretching within the carboxylic group. The peak detected at 1420 cm⁻¹ is assigned to C-O-H stretching within the plane, unambiguously confirming the presence of a carboxylic group. Furthermore, a pair of medium-intensity peaks emerged at 2978 cm⁻¹ resulting from C-H asymmetric and symmetric stretching within the methyl group, signifying the presence of methyl groups in the structure. The peak detected at 3455 cm⁻¹ wave numbers signifies the presence of out-of-plane aromatic -H stretching along with O-H vibrations.

Figure 2: FTIR spectra of (from top to bottom) - pure Ketoprofen, HPMC, PEG 400 and the physical mixture

During the compatibility study, the physical mixture of API combined with HPMC and PEG400 likewise featured matching peaks. These observations signified that no detrimental chemical reaction occurred between the study’s formulation components and the selected API.

Evaluation of Ketoprofen Transdermal Patches:

A visual examination of the drug-loaded transdermal patches assessed their colour clarity, flexibility and smoothness. Each of the patches was observed to be transparent, colourless, smooth, and clearly flexible. All the prepared formulations were found to exhibit uniform thickness values ranging from 0.433 mm to 0.438 mm. Additionally, the weights were consistently uniform. All the patches demonstrated a pH value close to neutral 6. The drug content of the patches ranged from 86.45–96.86 %. The collated data are presented in table 4.

Values are expressed as the Means ± SD, where (N = 3).

Moisture content and moisture uptake analyses supply data on the formulation’s stability (15). Across all four formulations, the percentage moisture uptake rose in correspondence with the escalating drug concentration ratio, namely F1 < F2 < F3 < F4 (Table 5). Moisture uptake data of the films measured at relative humidity levels of 75% and 95% have been presented.

Table 5: % Moisture content and % Moisture uptake of TD patches

TD patches	% Moisture uptake		Moisture content (%)
TD patches	Relative humidity 95%	Relative humidity 75%	Moisture content (%)
F 1	8.22± 0.56	4.32 ± 0.56	3.96 ± 0.86
F 2	9.78± 0.60	4.82 ± 0.60	2.67 ± 0.50
F 3	10.43± 0.77	5.68 ± 0.77	2.48 ± 0.31
F 4	6.29± 0.17	6.17± 0.17	2.31 ± 0.04

In vitro Drug Release Profile:

Among the formulations, F4 exhibited the highest drug release profile, whereas the patch F3 revealed the lowest drug release at the completion of six hours (Figure 3). The findings reveal that the most favorable release profile was produced by formulations F1 and F4, each containing 50:50 and 100:100 drug concentrations, respectively. Such results may be attributed to the equal dose intensities of the drug in each formulation. The release order of the drug was F4 > F1 > F2 > F3. Drug release from the transdermal patch followed a linear pattern during the first 4 hours, before reaching a steady state up to 6 hours. Prabhakara et. al. likewise recorded comparable findings (16).

Figure 3: Drug Release Profiles from Transdermal Patches

Stability studies:

In accordance with ICH guidelines, stability studies on the optimized formulation were performed at 40°C/75% RH for a period of six months. At the conclusion, the formulation was tested for thickness, drug content, moisture content, moisture uptake, appearance, and a diffusion evaluation. The findings are presented in Table 6.

Table 6: Evaluated data of optimized formula after 6 months

S. No.	Parameter	0 week	6 months
1	Thickness (mm)	0.23	0.25
2	Weight (mg/cm²)	22	23
3	Drug content (%)	97.89	95.88%
4	Moisture content (%)	2.81	2.95
5	Moisture uptake (at 75% RH)	5.64	5.92

These stability investigations revealed that all patches preserved strong physicochemical characteristics and sustained drug content after being stored in a variety of conditions.

CONCLUSION:

On the basis of the present investigation, it can be inferred that the transdermal formulation of ketoprofen with HPMC and FM fulfils the optimal profile of a transdermal device and can serve as a viable means to evade extensive hepatic first-pass metabolism, thereby enhancing bioavailability. Moreover, the ketoprofen transdermal patches furnished sustained transdermal release for extended periods, having been formulated with natural polymers derived from the seeds of Linum usitatissimum and thus proving suitable for the therapy of rheumatoid arthritis (RA). The experimental work carried out in this study reveals that natural polymers can be implemented with greater efficiency in modern dosage forms.

Thus, the results of this investigation imply that formulating a TD patch based on flaxseed mucilage and ketoprofen could represent a straightforward, affordable route to obtain a robust, effective arthritis treatment.

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Received on 07.08.2025 Revised on 30.08.2025

Accepted on 18.09.2025 Published on 18.10.2025

Available online from November 03, 2025

Res. J. Pharma. Dosage Forms and Tech.2025; 17(4):267-272.

DOI: 10.52711/0975-4377.2025.00037

This work is licensed under a Creative Commons Attribution-Non Commercial-Share Alike 4.0 International License. Creative Commons License.

TD patches	Weight Uniformity (gm)	Thickness (mm)	Surface pH	Folding Endurance (n)	Skin Irritancy	Drug (%) Content
F 1	0.1850 ± 0.002	0.434 ± 0.02	6	15 ± 2.60	No irritation	86.45 ± 0.84
F 2	0.1876 ± 0.003	0.435 ± 0.01	6	13 ± 2.50	No irritation	92.41 ± 1.12
F 3	0.1866 ± 0.002	0.433 ± 0.01	6	12 ± 3.21	No irritation	89.54 ± 0.73
F 4	0.1856 ±0.004	0.438 ± 0.03	6	17 ± 1.52	No irritation	96.86 ± 1.02