Formulation and Evaluation of Mouth Dissolving Films of Captopril by using Natural Polymers.

 

Pushkar S. Chavan*, Avish D. Maru, Majid S. Khan.

Loknete Dr. J. D. Pawar College of Pharmacy, Manur, Tal. Kalwan, Dist. Nashik, (MH) India.

 

ABSTRACT:

Mouth dissolving films (MDFs) of captopril were developed using natural polymers, including pectin, sodium alginate, and guar gum, in combination with the plasticizer polyethylene glycol 400 (PEG 400) and other ingredients like saliva stimulating agent, sweetener and super disintegrator etc. A total of nine formulations were prepared using different concentrations of the polymers by the solvent casting method. The objective of the study was to evaluate the suitability of these polymers and the effect of polymer concentration on the performance of the MDFs. The MDFs were evaluated based on various parameters, including folding endurance, dissolution, and disintegration studies. Among the different formulations, batch F4, which contained 50% (w/w) pectin as the polymer and 17% (w/w) PEG 400 as the plasticizer, exhibited satisfactory results. The folding endurance test indicated that batch F4 had good flexibility and strength, suggesting that it could withstand repeated folding without breaking or cracking. The in vitro dissolution study revealed that the MDFs of batch F4 exhibited rapid and complete drug release in 6 min, indicating their potential for enhanced drug delivery. The disintegration study further confirmed that the MDFs disintegrated within a short time, ensuring rapid disintegration and dissolution of the drug in the oral cavity.

 

 

 

1. INTRODUCTION:

In recent years, there has been an increasing demand for more patient-friendly methods of medication administration. Advancements in technology have provided effective alternatives for individuals who struggle with swallowing pills or liquids. Approximately 25% of the population faces difficulties in swallowing pills or capsules, which often leads to non-compliance with prescription instructions and inadequate treatment.

 

Sublingual or buccal administration of medication has long been recognised as a rapid and efficient way to deliver drug solutes directly into the bloodstream. However, oral administration remains the most widely used method due to its simplicity, painlessness, adaptability, and, most importantly, patient-friendly nature. One of the newer forms of oral medication is the oral strip, which is a thin film composed of hydrophilic polymers that dissolves rapidly on the tongue or inside the buccal cavity. These fast-dissolving drug delivery systems have gained popularity due to their user-friendly nature and their ability to enhance patient acceptance.¹

 

 

Mouth dissolving films (MDF), also known as oral strips, oral fast dissolving films (FDF), or orodispersible films (ODF),^[3] have a thin, elegant appearance and come in various sizes and shapes on the market. They can be consumed without water, which is highly beneficial for travel purposes, and there is no risk of choking since they dissolve when placed on the tongue. MDF can be used for local or site-specific effects in the oral mucosa.²

 

When a drug is dissolved or spread in saliva and then ingested, it is typically absorbed through the gastrointestinal tract as usual. As the saliva makes its way down to the stomach, some drugs are absorbed from the mouth, throat, and oesophagus, which may lead to a rapid onset of action. As a result, the bioavailability of the oral films is significantly greater than that observed with conventional tablet forms. ³

 

MDF is superior to tablets and liquids because it combines the best features of both solid and liquid dosage forms. It has fast dissolution and good bioavailability like a liquid, but it remains in a solid state with stability similar to that of a solid dosage form until it is consumed. ⁴

 

Captopril is an ACE inhibitor-class antihypertensive drug that is used to treat hypertension (high blood pressure), left ventricular dysfunction, after myocardial infraction, and diabetic nephropathy. The goal of current research is to develop a safe, effective, and convenient method of administering antihypertensive drugs to patients who are bedridden or suffer from dysphagia, as well as to paediatric and geriatric patients.

 

The film is generally created in the form of a large sheet and then cut into smaller doses that are suitable for packaging in various approved pharmaceutical formats.⁵

 

1.1 Importance of natural polymer:^{6, 22}

Natural polymers are now preferred over synthetic ones because they possess several advantages. They are environmentally friendly, compatible with living organisms, and harmless. They are also cost-effective, safe, and devoid of adverse reactions. Furthermore, natural polymers are readily accessible. Hence, their biodegradability, biocompatibility, non-toxicity, economic viability, safety, absence of side effects, and easy availability contribute to their superiority over synthetic polymers.

 

Fig. 1.0 Mouth dissolving film of Captopril.

 

2. MATERIALS AND INSTRUMENTS EMPLOYED:

2.1 Materials:

Captopril was purchased from Balaji Drugs, Nashik, Maharashtra, India. All other reagents were obtained from the research laboratory.

 

2.2 Instrumentation:

The work was done on the UV-visible spectrophotometer (Model EQ-826, Equiptronics). The FTIR spectra of API and its excipients were secure by Fourier Transform Infrared Spectrophotometer (Bruker). All weighing was done on an electronic precision balance (Wenser PGB220).

 

3. Formulation of Captopril Mouth Dissolving Films:^{4, 7}

Using the solvent casting method, nine different formulas (F1–F9) were prepared with varying percentages of polymer, as indicated in Table 1. Each film had a surface area of approximately 4 cm² and was loaded with 12.5 mg of captopril. To prepare the polymeric solution, the calculated amount of film-forming polymer was dispersed in 15 ml of distilled water and stirred continuously with a magnetic stirrer for 2 hours to achieve a homogeneous mixture. A plasticizer was then added to this mixture. In another beaker, the drug (captopril), citric acid (a saliva stimulating agent), sucrose (a sweetener), and other ingredients were dissolved in 5 ml of water to create a clear solution. The two solutions were mixed using a magnetic stirrer for 1 hour, then degassed in a sonicator and allowed to stand for at least 24 hours to remove any entrapped air bubbles. The bubble-free solution was then cast onto a petri dish and placed in a tray dryer at 50°C for 2–3 hours to evaporate the solvent. The resulting dried film was cut into the desired shape and size (4 cm²) for its intended use, excluding any cuts or imperfections from the study.

 

Table 1.0 Formulation Table for Captopril Mouth Dissolving Films:

Ingredients (mg)	F1	F2	F3	F4	F5	F6	F7	F8	F9
Captopril	12.5	12.5	12.5	12.5	12.5	12.5	12.5	12.5	12.5
Sodium alginate	50	60	70	-	-	-	-	-	-
Pectin	-	-	-	50	60	70	-	-	-
Guar gum	-	-	-	-	-	-	50	60	70
Polyethylene glycol- 400	17	17	17	17	17	17	17	17	17
Sodium starch glycolate	07	07	07	07	07	07	07	07	07
Citric acid	4.5	4.5	4.5	4.5	4.5	4.5	4.5	4.5	4.5
Sucrose	4.5	4.5	4.5	4.5	4.5	4.5	4.5	4.5	4.5
Vanillin	4.5	4.5	4.5	4.5	4.5	4.5	4.5	4.5	4.5
Distilled water	q.s.	q.s.	q.s.	q.s	q.s.	q.s.	q.s.	q.s.	q.s.

Note: All quantities are expressed in mg/film.

 

3.1. Dose calculation:

Radius of the petri dish: 4.60 cm.

Surface area petri dish: 66.48 cm².

Area of a single film: 4 cm².

The total number of films in the petri dish is 16.62.

A total of 16.62 films in one petri dish contain 207.75 mg of drug. Single film containing approximately 12.5 mg of drug.

 

4. RESULT AND DISCUSSION:

4.1. Pre-formulation study:

4.1.1. Characterization of physiochemical properties of drug:

Initially, after receiving the drug, the basic characteristics of the API were checked as described below.

 

4.1.1.1. Organoleptic properties:

Captopril is a white crystalline powder with a sulphide like odour; the entire drug's characteristic complies with official standards.

 

4.1.1.2. Determination of thePhysical constant (Melting Point):

The melting point was determined by the capillary method, and it was found to be in the range of 104–108 °C, which complies with I.P.

 

4.1.1.3. Solubility profile of the drug:

The solubility of the captopril was determined by using the shake flask method with the help of various solvents like water, methanol, and 0.01 N HCL. It was found to be freely soluble in all three solvents.

 

 

4.1.2. Analysis of drug by calibration curve method:⁸

The calibration curve of captopril was performed in 0.01 N HCL. The absorbance of the solution was measured at 203 nm using a UV-visible spectrophotometer.

·       Line Equation: y=0.026x + 0.0332

·       Regression Coefficient: R²=0.9955

 

Table 2.0 Concentration and Absorbance

Sr. no.	Concentration (In ppm)	Absorbance
1.	10	0.325
2.	20	0.509
3.	30	0.813
4.	40	1.079
5.	50	1.34

 

Fig. 2.0 Calibration curve of Captopril.

 

4.1.3. Stability study of Captopril with excipients:

4.1.3.1. Physical Observation:

All the mixtures of captopril and excipients observed physically.

 

Table 3.0 Compatibility Study of Captopril and Excipients

Sr. No.	Composition	Caking	Liquefaction	Discoloration	Odour	Conclusion
1.	Drug +Sodium alginate	No	No	No	No	Compatible
2.	Drug +Pectin	No	No	No	No	Compatible
3.	Drug +Guar gum	No	No	No	No	Compatible
4.	Drug +Polyethylene glycol- 400	No	No	No	No	Compatible
5.	Drug +Sodium starch glycolate	No	No	No	No	Compatible
6.	Drug +Citric acid	No	No	No	No	Compatible
7.	Drug +Sucrose	No	No	No	No	Compatible
8.	Drug +Vanillin	No	No	No	No	Compatible
9.	Drug +All ingredients	No	No	No	No	Compatible

 

4.1.3.2.    Drug Excipient Study by FTIR:⁹

The physical mixture of captopril and pectin was kept under compatibility study at 40 °C and 75 % RH for a period of two weeks. They were found to be without any significant physical changes. Therefore, it is confirmed that all the active and inactive excipients that were kept under compatibility study are compatible with each other. All these ingredients were selected and used in the present work.

 

 

Table 4.0: Interpretation of FTIR peak present in Captopril

Sr. No.	Characteristic Wave number range cm-1	Appearance of peak	Wave number in formulation (cm-1)	Bond nature and bond attributed
1.	2550-2600	Weak	2563.33	Thiol group (S-H Stretching)
2.	1760-1690	Strong	1743.91	Carboxylic acids (C=O Stretching)
3.	1500-1600	Strong	1585.29	Amide group (C=O Stretching)
4.	1440-1480	Medium	1469.32	Alkane (C-H Bending)
5.	1250–1020	Medium	1189.23	Aliphatic amines C–N stretch

 

 

Fig 3.0 FTIR Spectra of Captopril.

 

 

Fig 4.0 FTIR Spectra of Captopril + Pectin.

 

4.1.3.3. DSC study:¹⁰

Differential Scanning Calorimetry (DSC) is a thermal analytical technique that measures the heat against time and examines how the physical properties of a sample change with increasing temperature over time.

 

DifferentialScanning Calorimetry of Captopril:

The thermal analysis of captopril was carried out using DSC. The DSC curve of captopril shows a sharp exothermic peak at 111.94⁰c at 9.04 min.

 

 

Fig 5.0 Differential Scanning Calorimetry of Captopril.

 

Differential Scanning Calorimetry of Captopril and All Excipients:

 

 

Fig 6.0 Differential Scanning Calorimetry of Captopril and all Excipients.

 

4.2. Evaluation of captopril mouth dissolving films:

The captopril mouth dissolving films were evaluated for the following parameters:

a.     Organoleptic evaluation¹¹

b.     Film forming capacity¹²

c.     Thickness ¹³

d.     Folding endurance¹⁴

e.     Weight variation ^{15, 9}

f.      Surface pH¹⁶

g.     In vitro disintegration study^{17, 18}

h.     Drug content uniformity^{19, 4}

i.      In vitro dissolution study^{20, 4, 21}

 

 

4.2.1. Organoleptic evaluation:

Table No. 5.0 Organoleptic evaluation

Sr. no.	Polymer	Colour	Surface Texture	Sticky / Non-sticky	Films
1.	Sodium alginate	white	Rough	Non-sticky
2.	Pectin	Translucent	Smooth	Non-sticky
3.	Guar gum	Yellowish	Smooth	Non-sticky

 

4.2.2. Film forming capacity of polymers:

 

Table No. 6.0 Film forming capacity of polymer

Sr.No.	Polymer	Film Forming Capacity
1.	Sodium alginate	Poor
2.	Pectin	Good
3.	Guar gum	Average

4.2.3. The table below presents the results for the thickness, folding endurance, weight variation, surface pH, in vitro disintegration and drug content uniformity of films.

 

 

Table No. 7.0 The results for the thickness, folding endurance, weight variation, surface pH, in vitro disintegration and drug content uniformity:

Formulation Code	Thickness (mm)	Folding Endurance	Weight Variation (mg)	Surface pH	In-vitro DT (sec.)	Drug Content Uniformity (%)
F1	0.27 + 0.020	38 + 5.57	99.33 + 3.57	6.1 + 0.31	34.33 + 1.53	98.67 + 1.53
F2	0.296 + 0.012	51.33 + 4.04	111 + 4.36	6.7 + 0.21	38 + 2	91.33 + 6.81
F3	0.32 + 0.026	62.33 + 5.51	120.33 + 5.51	6.1 + 0.2	46.67 + 3.51	89.67 + 8.02
F4	0.233 + 0.006	91.33 + 4.73	98.66 + 4.04	6.2 + 0.15	25.67 + 2.08	96 + 1.73
F5	0.273 + 0.012	103 + 5.57	109.66 + 2.08	6.3 + 0.21	32.67 + 2.08	93.67 + 5.13
F6	0.316 + 0.015	117 + 4.51	121.66 + 4.51	6.3 + 0.31	37.33 + 1.53	95.67 + 2.52
F7	0.233 + 0.015	47 + 3.61	100.33 + 3.06	6.9 + 0.4	29 + 1.73	88.67 + 4.73
F8	0.28 + 0.020	58.66 + 5.69	108.33 + 6.66	6.5 + 0.15	36.33 + 2.08	94 + 1
F9	0.326 + 0.021	73 + 4.93	120.66 + 3.79	6.9 + 0.21	42.67 + 3.06	90.33  + 4.93

 

4.2.4. In-vitro dissolution study:

The in-vitro dissolution of captopril films was studied using a USP type I dissolution apparatus (basket) operating at a temperature of 37.0±2°C and a rotation speed of 50rpm. A basket apparatus was employed to ensure the film (4 cm²) loaded with 12.5mg of captopril dissolves appropriately in a dissolution jar. The jar was filled with 500ml of dissolution medium consisting of phosphate buffer 6.8. Samples were withdrawn at specific time intervals (1, 2, 3, 4, 5, and 6 minutes) and analysed for drug release using spectrophotometry at a wavelength of 203nm. To maintain sink conditions, the volume withdrawn each time was replaced with an equal volume of fresh 6.8 phosphate buffer. The cumulative percentage of captopril released was calculated and plotted against time.

 

Table 8.0 In-Vitro % Drug Release of Captopril in Phosphate Buffer 6.8

Time (min.)	F1	F2	F3	F4	F5	F6	F7	F8	F9
1	18.58	14.73	11.35	23.96	21.35	19.35	28.89	21.96	18.43
2	34.27	26.58	23.96	37.50	35.66	32.58	45.96	30.43	27.66
3	50.43	45.96	36.27	56.27	53.35	52.73	57.81	41.20	40.12
4	69.96	62.43	49.96	68.27	65.04	62.43	70.12	58.12	52.73
5	79.35	73.50	59.66	87.96	84.58	75.96	83.50	68.43	61.50
6	85.50	74.73	66.73	99.66	95.04	87.35	88.89	80.89	69.81

 

 

Fig 7.0 In-Vitro Drug Release of Batch F1 to F5

 

Fig 8.0 In-Vitro Drug Release of Batch F6 to F9

 

5. CONCLUSION:

On the basis of the obtained results, the use of natural polymers such as pectin, sodium alginate, and guar gum, along with the plasticizer PEG 400, in the formulation of mouth-dissolving films of captopril showed promising results. Among the various formulations evaluated, batch F4 emerged as the most suitable choice for preparing captopril films. This particular formulation contains 50% (w/w) pectin and 17% (w/w) PEG 400, which have proven to be effective in achieving the desired outcomes. The F-4 formulation exhibited a folding endurance of 91, indicating its durability during handling. In-vitro dissolution studies demonstrated a rapid drug release rate of 99.66% within 6 minutes, while the films disintegrated in just 25 seconds. These findings highlight the significant potential of utilising natural polymers like pectin for the development of highly effective and patient-friendly oral drug delivery systems.

 

6. ACKNOWLEDGEMENT:

We are thankful to the teacher’s and Principal of LokneteDr. J. D. Pawar College of Pharmacy, Manur, Tal. Kalwan for their helpful guidance.

 

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Received on 01.06.2023         Modified on 05.08.2023

Accepted on 01.09.2023   ©AandV Publications All Right Reserved