Formulation and Evaluation of Fast Dissolving Tablets of Chlorpromazine Hydrochloride Using Novel Co-processed Superdisintegrants

 

Satyajit S. Deshmukh*, Aamer Quazi, Ashish Saraf

K. T. Patil College of Pharmacy, Osmanabad-413501, Maharashtra, India.

*Corresponding Author E-mail: satyajitdeshmukh212@gmail.com

 

ABSTRACT:

The demand for mouth dissolving tablet (MDT) has been growing during the last decade especially for elderly and children who have swallowing difficulties. Chlorpromazine HCl is a potent anti-emetic, act by blocking D2 receptors in the Chemoreceptor trigger zone (CTZ) and antagonize apomorphine induced vomiting. In the present work, fast dissolving tablets of Chlorpromazine HCl were prepared by direct compression method using novel co-processed superdisintegrants consisting of crospovidone and sodium starch glycolate in the different ratios (1:1, 1:2 and 1:3). The developed superdisintegrants were evaluated for angle of repose, Carr’s index and Hausner’s ratio in comparison with physical mixture of superdisintegrants. The angle of repose of the developed excipients was found to be < 25°, Carr’s index in the range of 10-15% and Hausner’s ratio in the range of 1.11-1.14. Fast dissolving tablets of Chlorpromazine hydrochloride were prepared using the above co-processed superdisintegrants and physical mixtures of superdisintegrants evaluated for pre-compression and post-compression parameters. The drug-excipients interaction was checked and found negative through IR and DSC studies. Among all the formulations CP1 containing co-processed superdisintegrants of crospovidone and sodium starch glycolate in ratio 1:1 was found to be promising and has shown an in-vitro dispersion time of 19 sec, wetting time of 24 sec, almost complete release of drug within 8 minutes. Finally it was concluded that FDT of Chlorpromazine hydrochloride can be successfully formulated by direct compression method with improved patient compliance.

 

 

INTRODUCTION:

Despite of tremendous advancements in drug delivery, the oral route remains the perfect route for the administration of therapeutic agents because the low cost of therapy and ease of administration lead to high levels of patient compliance.¹ Among the pharmaceutical dosage forms conventional tablets are popular because of their special properties such as suitability to self administration, improved stability, accurate dosing, ease of handling, versatility with respect to type and dose of the drug and suitability to scale up.²Difficulty in swallowing (dysphagia) is common among all age groups, especially in elderly, and is also seen in swallowing conventional tablets and capsules. This problem can be solved by developing rapidly disintegrating and fast dissolving tablet dosage forms for oral administration because they dissolve in saliva and does not require water for swallowing.

 

A fast disintegrating or dissolving system or tablet can be defined as a solid dosage form that can disintegrate or dissolve within a matter of seconds, in the oral cavity resulting in a solution or suspension without administration of water. The disintegration time for fast dissolving tablet varies from a few seconds to more than a minute depending on the formulation and the size of the tablet. FDTs are also called as mouth dissolving tablets; melt in mouth tablets, rapimelts, porous tablets, orodispersible, quick dissolving or rapidly disintegrating tablets³. Their growing importance was underlined recently when European pharmacopoeia adopted the term “Orodispersible tablet” [ODTs] as a tablet that to be placed in the mouth where it disperses rapidly, before swallowing. United States Food and Drug Administration (FDA) defined ODT as “A solid dosage form containing medicinal substance or active ingredient which disintegrates rapidly usually within a matter of seconds when placed upon the tongue.^4,5

 

Major challenge for tablets and capsule manufacturing comes from the flow properties of the materials to be compressed. Most of the formulations (> 70%) contain excipients at higher concentration than active drug.

 

In recent years drug formulation scientists have recognized that single-component excipients do not always provide the requisite performance to allow certain active pharmaceutical ingredients to be formulated or manufactured adequately. Hence, there is a need to have excipients with multiple characteristics built into them such as better flow, low/no moisture sensitivity, superior compressibility and rapid disintegration ability. One such approach for improving the functionality of excipients is co-processing of two or more excipients. Co-processing is based on the novel concept of two or more excipients interacting at the sub particle level, the objective of which is to provide a synergy of functionality improvement as well as masking the undesirable properties of individual. Co-processing excipients leads to the formulation of excipients granules with superior properties compared with physical mixtures of components or individual components⁶. In the present investigation, the preparation and evaluation of fast dissolving tablets of Chlorpromazine hydrochloride by using co-processed superdisintegrants containing crospovidone and sodium starch glycolate was studied. The reasons for selection of crospovidone are high capillary activity, pronounced hydration capacity and little tendency to form gels. Sodium starch glycolate was chosen because of its high swelling capacity. Chlorpromazine HCl is chemically{3-(2- chlorophenothiazin-10yl)} dimethylamine HCl. Chlorpromazine HCl is a potent anti-emetic, act by blocking   D2 receptors in the Chemoreceptor trigger zone (CTZ), and antagonize apomorphine induced vomiting⁷. In the present study, an attempt had been made to prepare fast dissolving tablets of Chlorpromazine HCl using co-processed superdisintegrants in the oral cavity with enhanced dissolution rate and hence improved patient complianc ⁸.

 

MATERIALS AND METHODS:

Materials:

Chlorpromazine HCl was received as a gift sample. Crosspovidone, sodium starch glycolate, microcrystalline cellulose, mannitol, magnesium stearate, aspartame, talc were obtained as gift samples from Loba chemicals Pvt Ltd, Mumbai and FDC Pvt Ltd, Mumbai. All other chemicals used were of analytical reagent grade.

 

Methods:

Preparation of co-processed superdisintegrants^9,10

The co-processed superdisintegrants were prepared by solvent evaporation method. A blend of crospovidone and sodium starch glycolate (in the ratio of 1:1, 1:2 and 1:3) was added to 10 ml of ethanol. The contents of the beaker (250 ml capacity) were mixed thoroughly and stirring was continued till most of ethanol evaporated. The wet coherent mass was granulated through # 44-mesh sieve. The wet granules were dried in a hot air oven at 60º C for 20 minutes. The dried granules were sifted through # 44- mesh sieve and stored in airtight container till further use.

 

Formulation of fast dissolving tablets of Chlorpromazine Hydrochloride by direct compression method¹¹

Fast dissolving tablets of chlorpromazine hydrochloride were prepared by direct compression, using novel co-processed superdisintegrants consisting of crospovidone and sodium starch glycolate in the different ratios (1:1, 1:2 and 1:3) according to the formula given in table no: 1. All the ingredients were passed through #60 mesh separately. The drug, co-processed superdisintegrants, Avicel PH 102 (directly compressible microcrystalline cellulose), mannitol, aspartame and talc were weighed and mixed in geometrical order. Finally magnesium stearate was added, mixed and blended well with the initial mixture. The mixed blend of drug and excipients was compressed using multitooling tablet punching machine to produce tablets weighing 150 mg each.

 

Evaluation of fast dissolving tablets of Chlorpromazine Hydrochloride

Thickness¹²

Thickness of the tablet is important for uniformity of tablet size. Thickness was measured using Vernier Calipers. Thickness of five tablets from each batch was measured and mean was calculated.

 

Hardness test^13,14

The resistance of tablets to shipping or breakage under conditions of storage, transportation and handling before usage depends on its hardness. The hardness of each batch of tablet was checked by using digital hardness tester. The hardness was measured in terms of kg/cm². Three tablets were chosen randomly and tested for hardness.  The average hardness of 3 determinations was recorded.

 

Table (1):Composition of Chlorpromazine Hydrochloride Fast Dissolving Tablets

 

 

Figure (1): Simple method for the measurement of wetting time of a tablet.

 

Weight Variation Test¹⁴

Twenty tablets were weighed individually and all together. Average weight was calculated from the total weight of all tablets. The individual weights were compared with the average weight. The percentage difference in the weight variation should be within the permissible limits (±7.5%). The percent deviation was calculated using the following formula.

                                          Individual weight – Average weight

Percentage Deviation =-------------------------------------------------x 100

                                                            Average weight

Friability Test¹⁵

Friability is the loss of weight of tablet in the container/package, due to removal of fine particles from the surface. This in process quality control test is performed to ensure the ability of tablets to withstand the shocks during processing, handling, transportation, and shipment. Roche friabilator (Electrolab, Mumbai) was used to measure the friability of the tablets.

 

Twenty (20) tablets were weighed and the initial weight of these tablets was recorded and placed in Roche friabilator and rotated at the speed of 25 rpm for 100 revolutions. 

 

Then tablets were removed from the friabilator, dusted off the fines and reweighed and the weight was recorded.

 

Percentage friability was calculated by using the formula:-

% Friability =	Initial weight of  – Final weight of the tablets                                  the tablets	X 100
	Initial weight of the tablets

% Friability of tablets less than 1% is considered acceptable.

Drug Content Uniformity¹⁶

Powder one or two tablets and weigh accurately powder equivalent to 10mg of chlorpromazine HCl. Shake with 1 ml of dilute hydrochloric acid and 40 ml of water for 15 minutes, add sufficient water to produce 100ml and mix. Centrifuge about 15 ml and to 10.0 ml of the clear, supernatant liquid add 2 ml of 1M hydrochloric acid and sufficient water to produce a solution containing about 0.0005% w/v of Chlorpromazine Hydrochloride. Measure the absorbance of the resulting solution at the maximum at about 254 nm Determine the drug content spectrophotometrically at l_max 254nm using calibration curve.

 

Water Absorption Ratio¹⁷

A piece of tissue paper folded twice was placed in a small petridish containing 10 ml of water. A tablet was put on the paper and time required for complete wetting was measured. The wetted tablet was then weighed. Water absorption ratio, R was determined using following equation.

R = 100 x [W_a – W_b] / W_b

Where, W_a = weight of tablet after absorption

W_b = weight of tablet before absorption

 

Wetting Time¹⁷

A piece of tissue paper folded twice was placed in a small petridish (i.d. = 6.5 cm) containing 10 ml of water. A tablet was placed on the paper, and the time required for complete wetting was measured. The time required for water to reach upper surface of the tablet is noted as wetting time (Figure-1)

 

In Vitro Dispersion Time¹⁸

The dispersion time was measured using a modified method (n = 3). For this purpose, a petri dish (10-cm diameter) was filled with 10 ml of water. The tablet was carefully put in the center of the petri dish and the time for the tablet to completely disintegrate into fine particles was noted. 

 

In Vitro Dissolution Studies¹⁹

In vitro dissolution studies were carried out by using USP Type I Dissolution Apparatus (Basket Type) at 50 rpm using 900ml of 0.1 N HCl as dissolution medium. Temperature of the dissolution medium was maintained at 37±0.5°C. Aliquots of 5 ml of dissolution medium were withdrawn at different time intervals; the fresh dissolution medium was replaced every time with the same quantity of the sample.

 

Table (2): Pre-compression Parameters of Co-processed Superdisintegrants and Physical Mixture of Superdisintegrants

Formulation Codes	Parameters
	Bulk density(gm/cm3)	Tapped density(gm/cm3)	Angle of repose (degree)	Carr’s index (%)	Hausner’s ratio
PM1	0.49	0.57	29.28	14.03	1.16
PM2	0.55	0.64	29.13	14.06	1.16
PM3	0.53	0.62	28.96	14.51	1.16
CP1	0.32	0.36	24.23	11.11	1.12
CP2	0.37	0.42	23.41	11.90	1.13
CP3	0.39	0.45	23.88	13.33	1.15

 

Table (3): Pre-compression Parameters of Chlorpromazine HCl FDT Formulations Prepared by Direct Compression Method

Formulation Codes	Parameters
	Bulk density(gm/cm3)	Tapped density(gm/cm3)	Angle of repose (degree)	Carr’s index (%)	Hausner’s ratio
CP0	0.69	0.81	32.84	14.81	1.17
PM1	0.58	0.68	29.91	14.70	1.17
PM2	0.66	0.77	29.58	14.28	1.16
PM3	0.64	0.75	29.21	14.66	1.17
CP1	0.38	0.43	28.05	11.62	1.13
CP2	0.46	0.53	28.63	12.96	1.15
CP3	0.47	0.54	27.97	12.93	1.14

 

Table (4): Post-compression Parameters of Chlorpromazine HCl FDT Formulations

 

The collected samples were analyzed by measuring the absorbance at 254 nm by UV Spectrophotometer. The cumulative percentage drug release was calculated.

 

RESULTS AND DISCUSSION:

Co-processed superdisintegrants were prepared by solvent evaporation using crospovidone and sodium starch glycolate in different ratios (1:1, 1:2. and 1:3).The developed co-processed superdisintegrants were evaluated for their flow and compression properties in comparison with physical mixture of superdisintegrants. The angle of repose of co-processed superdisintegrants was found to be <25^o which indicate excellent flow in comparison to physical mixture of superdisintegrants (<30o) due to granule formation, Carr’s index in the range of 10-15% and Hausner’s ratio in the range of 1.11 to 1.16. Co-processed superdisintegrants were found to be superior in flow and compression properties in comparison with physical mixture of superdisintegrants as shown in the table (2).

Fast dissolving tablets of chlorpromazine hydrochloride were prepared using above co-processed superdisintegrants and physical mixtures of superdisintegrants. Directly compressible mannitol (Pearlitol SD 200) was used as a diluent to enhance mouth feel. A total of six formulations and control formulation CP0 (without superdisintegrants) were designed. These tablets were evaluated for pre-compression parameters such as bulk density, tapped density, angle of repose,Carr’sindex, Hausner’s ratio and post-compression parameters such as hardness, thickness, friability, weight variation, in-vitro dispersion time, wetting time, water absorption ratio and drug content uniformity.

 

As the blends were free flowing (angle of repose <30⁰ and Carr’s index <15% Table 3), tablets obtained were of uniform weight (due to uniform die fill), with acceptable variation as per IP specification i.e., below 7.5%. Drug content found to be in the range of 96 to 100%, which is within acceptable limits.

 

Table (5):  In-vitro Dissolution Parameters in 0.1N HCl

CP₀ is control formulation, CP₁ is promising fast dissolving tablet formulation, PM₁ is formulation containing physical mixture of superdisintegrants in 1:1 ratio, D₄ is percent drug released in 4 min, D₈ is percent drug release in 8 min, D₁₂ is percent drug release in 12 min, D₁₈ is percent drug release in 18 min. t_50% is time for 50% drug dissolution, t_90% is time for 90% drug dissolution.

 

 

Figure (2): Comparison of the Dissolution studies of Chlorpromazine HCl FDT formulations.

 

Hardness of the tablets was found to be in the range of 3-3.60 kg/cm². Friability below 1% was an indication of good mechanical resistance of the tablets.  In-vitro dispersion time, water absorption ratio and wetting time, which are important criteria for understanding the capacity of disintegrants to swell in presence of little amount of water were found to be in the range of 19-107 sec, 41-87% and 26-125 sec respectively. Among all the designed formulations, formulation CP₁ was found to be promising and displayed an in vitro dispersion time of 19.33 sec, which facilitates its faster dispersion in the mouth.

 

Overall, the formulation CP₁ containing co-processed superdisintegrant (1:1 mixture of crospovidone and sodium starch glycolate) was found to be promising and has shown an in vitro dispersion time of 19.33 sec, wetting time of 26.33 sec and water absorption ratio of 86.91% when compared to the formulation PM₁ containing of physical mixture of superdisintegrants (1:1 mixture of crospovidone and sodium starch glycolate) which shows 43.66 sec, 50 sec and 65.69% values respectively and control formulation (CP₀) which shows 106 sec, 124 sec and 41.68% values respectively for the above parameters as shown in table (4).

 

In vitro dissolution studies on the promising formulation CP₁, PM₁, CP₂, CP₃, PM₂, PM₃ and control formulation (CP₀) were carried out in 0.1N HCl. The various dissolution parameter values viz., percent drug dissolved in 4 min, 8 min and 12 min, 18 min (D₄, D₈ and D₁₂, D₁₈), t_50%,   and t_90% are shown in Table (5) and dissolution profile depicted in figure (2). The results are shown in table20 and 21 and dissolution profile depicted in figure-2.This dissolution data reveals that CP₁ has shown faster drug release (99.67 within 8min) in 0.1N HCl as compared to other batches of Chlorpromazine HCl FDT formulations and the formulation CP₁ has shown nearly five fold faster drug release (t_50% 1.50 min) when compared to CP₀ (t_50% 10 min).

 

CONCLUSION:

In the present research work fast dissolving tablets of Chlorpromazine Hydrochloride were prepared by direct compression method using novel co-processed superdisintegrants. Co-processed superdisintegrants consisting of crospovidone and sodium starch glycolate exhibit good flow and compression characteristics. Fast dissolving tablets of Chlorpromazine Hydrochloride containing co-processed superdisintegrants exhibit quick disintegration and improved drug dissolution. It can be concluded from the present work that co-processed superdisintegrants of crospovidone and sodium starch glycolate are superior to physical mixtures of crospovidone and sodium starch glycolate used in Chlorpromazine HCl fast dissolving tablets.

 

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Received on 01.08.2012       Modified on 22.08.2012

Accepted on 02.09.2012      © RJPT All right reserved