Introduction
Haloperidol, a butyrophenone, is widely used neuroleptic. Though haloperidol is well absorbed after oral dosing, there is a first pass metabolism leading to a reduced bioavailability of the drug (60-70%). Therefore, the present investigation is concerned with the development of fast dispersible oral films of haloperidol.
Haloperidol preparations available in the market are in the form of tablets, suspension and suppositories. The fast dispersible films will be intended to meet the requirements of providing fast dissolution and pleasant mouth feeling to the patient. Thus, such a dosage form will not only suppress vomiting, but it will also be convenient and acceptable to use. Such a dosage form will be beneficial to the geriatric and pediatric patients, certain young individuals with underdeveloped muscular and nervous system, mentally ill and developmentally disabled patients, non co operative patients, people who are bed ridden, people who do not have access to water (e.g. travelers and army men). Various methods currently employed to produce fast dispersible films are Solvent casting, Semisolid casting, hot melt extrusion, Solid dispersion extrusion, and rolling.1
The present study included solvent casting method for formulation of fast dissolving film as it is the most popular and cheap method. The present study was aimed at developing fast dispersible films, which would include.
(a) A water soluble film former to disintegrate the film rapidly & a sweetener to mask bitter taste of drug.
(b) Auxiliary ingredients like plasticizers and surfactants. The film when placed in mouth, it will disintegrate and dissolve giving a rapid onset and pleasant mouth feels.
The development of a new pharmaceutical formulation by trial and error technique leads to a satisfactory formulation rather than an optimal one. The optimization techniques, on the basis of a few experiments and statistical analysis of the results can provide an efficient and economical method for prediction of the optimal composition.
Hence the present research work was designated towards formulation development of fast dispersible films of Haloperidol that possesses acceptable taste, mechanical strength and rapid disintegration to provide desired drug release property and pleasant mouth feel, for improving patient compliance, especially in pediatric and geriatric population. The concept of mouth dissolving drug delivery system emerged from the desire to provide patient with more conventional means of taking their medication. It is difficult for many patients to swallow tablets and hard gelatin capsules.
Hence, they do not comply with prescription, which results in high incidence of non-compliance and ineffective therapy. In some cases such as motion sickness, nausea, vomiting or coughing and unavailability of water, swallowing conventional tablets may be difficult. Such problem can be resolved by means of fast dispersing films when put on tongue these films disintegrate and dissolved rapidly in saliva without need of drinking water.2
The faster the drug disintegrates in to solution, the quicker the absorption and onset of clinical effect. Some drugs are absorbed from the mouth, pharynx and esophagus as saliva passes down into stomach. In such case, bioavailability of drug is significantly greater than those observed from conventional tablet dosage form.3
Materials and Methods
Materials
Haloperidol pure drug sample was generously gifted by Cypco Company ,Rau, Indore (M.P). Hydroxymethyl cellulose (HPMC) from Qualichem. Xanthan Gum from LOBA Ltd. PEG from HIMEDIA. Citric Acid from Merck Ltd. Sacrolose from Zydus Pharmaceuticles, Ahmedabad. Menthol from Raj Shah Pharmaceuticles. Methanol and water used were analytical grade.
Method
Melting point
Melting point of drug sample was determined by using melting point apparatus. The drug sample was taken and placed in a thin walled capillary tube; the tube was approximately 10-12 cm in length with 1mm in diameter and closed at one end. The capillary was placed in melting point apparatus and heated and when drug sample was melted the melting point of sample powder was recorded.4 The melting point of Haloperidol is shown in the table 5.3.2.
Identification of drug by
UV Spectroscopic characterization
Identification of the drug, Haloperidol was done by UV Spectrophotometric method using Systronics Spectrophotometer 2201. A standard stock solution of Haloperidol (100μg/ml) was prepared by dissolving 10mg of drug in 10 ml of methanol in a 100ml of volumetric flask and then volume was made upto mark with phosphate buffer (pH 7.4). The dilutions of this stock solution (100μg/ml) were made by diluting the required aliquot with phosphate buffer to obtain standard solutions in the range of 2- 20μg/ml. An UV spectroscopic scanning (200– 400nm) was carried out with drug solutions to determine the wavelength of maximum absorption (ʎmax) using same diluent as blank. 5 The UV spectrum of Haloperidol drug is shown in fig. 5.3.3.
Preparation of calibration curve of haloperidol
Standard curve of Haloperidol in phosphate buffer pH 7.4 at 247 nm was plotted using various concentrations against the absorbance values found at respective concentrations. The standard curve of Haloperidol was found to be linear in the range of 2-20 μg/ml, which means that present drug sample was obeying Beers- Lamberts range (2-20 μg/ml) and coefficient of correlation was found to be 0.999. 6 The observations of calibration curve are shown in table 5.3.4. The calibration curves of Haloperidol are.Figure 4, Figure 5, Figure 6
Preparation of simulated saliva
The ingredients mentioned in table 5.4 were dissolved in 1 liter of distilled water and pH was adjusted to 7.4 with Sodium Hydroxide.
Partition coefficient
Partition Coefficient of Haloperidol was determined by simple shaking flask method. 10 mg of drug was dissolved in 25 ml of distilled water and 25 ml of octanol in the separating flask. The flask was stoppered and shaken for 1 hr and kept aside for phase separation for at least 24 hrs to attain equilibrium. Two phases of octanol and water sample was separated by separating funnel. Aqueous phase containing Haloperidol was filtered through whatman filter paper. The filtered aliquote was measured spectrophotometrically after suitable dilution at 247 nm. The partition coefficient was measured by the given fomulea.7
The value of partition coefficient is shown in the table: 5.3.6.
Drug-excipient compatibility
Drug-excipient compatibility tests were performed to model for clinical and commercial development a chemically stable formulation. In preformulation, drug-excipient compatibility tests are performed to identify the most suitable excipients, test the compatibility of the active ingredients with the selected excipients, and prove that the chosen excipients are compatible with the active ingredient. In the chosen proportions, the active ingredients and the excipients are combined with a mortar and pestle. The mixtures are transferred into glass vials and sealed. The samples were kept at 40°C+2°C/75%±5% RH for four weeks. 8 The samples were analyzed for physical and chemical incompatibilities (Table 5.3.7)
Formulation of fast dissolving films
In the present study fast dissolving films of Haloperiol were prepared by solvent casting technique. Flat, square-shaped, aluminum foil-coated glass molds with 6.25 cm² surface area were used for casting the films.
Weighed quantities of polymers (HPMC) and Xanthan gum was separately kept for swelling overnight in 5 ml distilled water and dissolved. The drug and aspartame were added to the HPMC solution directly in formulation F1 to F3 while in Xanthan gum solution in formulation F4 to F8 along with glycerol as a plasticizer and mixed thoroughly to form a homogenous mixture. Finally, the polymer solution was added to the Xanthan gum solution, and volume made up to 10 ml with distilled water. Entrapped air bubbles were removed by applying vacuum. 9
Table 2
Formulation of fast dissolving film of Haloperidol
Weight variation
Mouths dissolving oral films were weighed on a digital balance, and the average weight was determined for each film. It is desirable that films should have nearly constant weight. It is useful to make sure that a film contains the right amount of excipients and API. 10
Thickness of Films
By using micrometer screw gauge, the thickness of the film was measured at 5 totally different places; an average of 3 values was calculated. This is essential to ascertain uniformity within the thickness of the film which is directly associated with the accuracy of dose within the film. 11
Folding endurance
The folding endurance is expressed as the number of folds (number of times the film is folded at the same place) required to break the specimen or to develop visible cracks. This also indicates the brittleness of the film. A strip of 2.5 cm x 2.5 cm was subjected to folding endurance by folding the film at the same place repeatedly several times until a visible crock was observed, and the values were reported.
Drug content uniformity
The prepared fast-dissolving film was dissolved in 10ml methanol and 40ml PBS pH 7.4 mixtures and filtered through Whatman filter paper. After suitable dilutions, the concentration of the drug was determined by measuring the absorbance at 247 nm.
Surface pH
The film to be tested was placed in a Petri dish and was moistened with 0.5 ml of distilled water and kept for 30s. The pH was noted after beinging the electrode of the pH meter in contact with the surface of the formulation and allowing equilibration for 1 min. The average of these determinations for each formulation was done. 12
In vitro Disintegration time
Disintegration time is the time when an oral film starts breaking when brought in contact with water or saliva. For a fast-dissolving film, the time of disintegration should be in the range of 5-30 s. The test was performed with disintegration test apparatus. 6.25 cm³ film was placed in the basket, raised and lowered in such a manner that the complete up and down rate equivalent to thirty times a minute. The time required by the film when no traces of film remain above the gauze was noted.13
In vitro Dissolution study
In vitro Dissolution study was carried out using USP type II basket type appatarus with PSB 7.4 as a dissolution medium. The temperature was maintained at a 37±0.50C with 50 rotation per minute 5 ml of aliquots were withdrawn at different time interval and same amount of fresh dissolution medium was replaced to maintain sink condition. The aliquots were analyzed for drug content for λ max 247 nm wavelength using UV-spectrophotometer. 14 The cumulative percentage drug release was calculated and reported.
Stability Studies
The stability study of the formulated fast-dissolving films was carried out under different environmental conditions of 2-8°C (45% RH), 25-30°C (60% RH), and 45-50°C (75% RH) for a period of 45 days.15 The films were characterized for the drug content during the stability study period.
Results and Discussion
UV Spectroscopy
The λ max of Haloperidol was obtained at 247 nm. This found to be similar as given in the reference. 17 Which shows that drug is pure. The UV spectrum of Haloperidol drug is shown in the Figure 5.
C. Preparation of standard Calibration curve of Haloperidol in Phosphate buffer pH 7.4 (λmax 247 nm)
Calibration curve of Haloperidol was prepared in phosphate buffer pH 7.4 at 247 nm. The absorbance values (mean of three determinations) with their standard deviation at different concentration in the range of 2-20 µg/ml for phosphate buffer pH 7.4 are tabulated. The drug obeys Beer’s Lambert law in the concentration range. Linear regression analysis for all calibration curves of Haloperidol is given in Table. So, this equation was used for the calculation of the solubility of the drug in different solvent, drug content and drug release. 18 The calibration curve of Haloperidol is shown in Figure 6.
Table 4
Data of standard calibration curve of Haloperidol in phosphate buffer 7.4
|
S. No. |
Concentration (µg/ml) |
Absorbance (nm) |
|
1. |
0 |
0 |
|
2. |
2 |
0.103 |
|
3. |
4 |
0.178 |
|
4. |
6 |
0.261 |
|
5. |
8 |
0.362 |
|
6. |
10 |
0.440 |
|
7. |
12 |
0.515 |
|
8. |
14 |
0.607 |
|
9. |
16 |
0.691 |
|
10. |
18 |
0.768 |
|
11. |
20 |
0.846 |
Partition coefficient
The LogP value of Haloperidol was found be 8.5. 19 The value is recorded in the table: 6.
Drug-excipient compatibility
Table 6
Drug excipients compatibility
Evaluation of Fast Dissolving Film of Haloperidol
Table 7
Thickness, folding endurance, drug content and surface ph of fast dissolving film of haloperidol
In vitro Disintegration time
Disintegration test for all prepared formulations was carried out using disintegration test apparatus. F1-F8 showed a disintegration time of 8 to 25 sec. From the results obtained, by increasing the concentration of polymer, disintegration time was increased. The disintegration time of F8 was found to be 8 seconds which took less time as compared to all other formulations (F1-F8). From the results obtained from the above formulations, another thanF5, F6, F8 disintegration time of all films was found to be within the limit as 5-30 seconds as per specification (USP 2007). Based on the disintegration time alone, F8 can be lead to develop as fast dissolving film (Table 9).
In vitro drug release study
From the in vitro drug release, it was observed that in formulations containing a single polymer, the drug release was found to be faster and films formed of HPMC resulted in a fastest release of drug. Further, as the concentration of the polymer increased, the drug release was found to be decreased due to the increase in the time required for wetting and dissolving the drug molecules present in the polymer matrices. The drug release was found to be in the following order. F1>F2>F4>F3>F5>F6. For the group of formulations containing a combination of polymers, the drug release was found to be in the following order: F7>F8>F9. Among the eight formulations (F1 to F8) prepared, formulations F8, F7, and F4 were found to be the best formulations in terms of drug release.
Table 9
In vitro drug release
Stability study
Stability study for the prepared film was carried out for 45 days at different temperature and humidity conditions. Fast-dissolving films were found to be physically and chemically stable as they showed no significant change in terms of physical characteristics and drug content at a lower temperature and room temperature. However, when stored at 45- 50°C for 45 days, films became brittle.
Table 10
Stability of formulations
Summary and Conclusion
Haloperidol fast dissolving films have been successfully prepared by solvent casting method. Haloperidol an anti-psychotic drug was selected for the preparation of fast dissolving films. HPMC and Xanthan gum were used as polymers for the preparation of Haloperidol fast dissolving films. Based on this physiochemical characterization in vitro drug release studies of Haloperidol showed 99% of drug at the end of 8th minutes. The evaluation test for films of Haloperidol suggest that it is promising to be developed as fast dissolving films with above mentioned excipients which can enhance the release of drug and thereby the bioavailability may be improved.
Acknowledgment
I am thankful to the management of Shri Bherulal Pharmacy Institute, Indore. For providing necessary facilities to carry out the research work and heartily thankful to my guide Dr. Neeraj Sharma and Co-guide Ms. Komal Tikariya for providing all the support and encouragement to carry out this studies.
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