DEVELOPMENT AND OPTIMIZATION OF FAST DISSOLVING TABLETS OF PROMETHAZINE THEOCLATE USING 32 FULL FACTORIAL DESIGN

DEVELOPMENT AND OPTIMIZATION OF FAST DISSOLVING TABLETS OF PROMETHAZINE THEOCLATE USING 3² FULL FACTORIAL DESIGN

Shiv Shankar Hardenia ^*1 and G N Darwhekar ²

Department of Pharmaceutics ¹, Suresh Gyan Vihar University, Jaipur, Rajasthan, India.

Acropolis Institute of Pharmaceutical education and Research ², Indore, Madhya Pradesh, India.

ABSTRACT: This research work aimed at developing and optimizing fast dissolving tablets of Promethazine Thecolate by direct compression technique. In the investigation, a 3² full factorial design was used to investigate the joint influence of two formulation variables (amount of superdisintegrants): amount of sodium starch glycolate and crospovidone. The tablets were evaluated for its percent friability and their disintegration time. The results of multiple linear regression analysis revealed that for obtaining a rapidly disintegrating dosage form, tablets should be prepared using an optimum concentration of sodium starch glycolate and a crospovidone. A contour plot was also presented to graphically represent the effect of the independent variables on the disintegration time 30 s and percent friability 0.5 %. A checkpoint batch was also prepared to prove the validity of the evolved mathematical model. The optimized tablet should be prepared with an optimum amount of Sodium starch Glycolate (2.75 mg), and Crospovidone (2.72 mg) which disintegrated in the 30 seconds, with friability of 0.5% and of drug release within 5 min. The optimized approach aided both the formulation of fast dissolving tablets and the understanding of the effect of formulation processing variables on the development of formulation.

Fast dissolving tablet,

Promethazine Thecolate, factorial design, Response Surface, contour plot.

INTRODUCTION: The oral route of administration still continues to be the most preferred route due to its manifold advantages including ease of ingestion, pain avoidance, versatility and most importantly patient compliance. The most popular solid dosage forms are tablet and capsule. One drawback of these dosage forms however is the difficulty to swallow. Dysphasia or difficulty in swallowing is seen nearly 35% in the general population.

This disorder is also associated with number of medical conditions including stroke, Parkinson’s disease, AIDS, head and neck radiation therapy and other neurological disorders including cerebral palsy.^1-3

Many elderly persons will have difficulties in taking conventional solid dosage form (tablets and capsules) because of their hand tremors and dysphasia. Swallowing problems are also common in young individuals because of their under developed muscular system. Other groups, who may experience problems in swallowing solid dosage form, are the mentally ill, the developmentally disabled, uncooperative patients and reduced liquid intake plans or nausea. In some cases such as motion sickness, sudden episode of allergic attack or coughing and an unavailability of water, swallowing of tablets may become difficult.⁴

To fulfill these medical needs, the pharmaceutical technologist have devoted considerable effort to develop a novel type of dosage form for oral administration, the Fast Dissolving Tablet (FDT), tablet that disintegrates and dissolves rapidly in saliva without need of water. The fast dissolving tablets usually dissolve in oral cavity within 15 to 60 s. The faster the drug goes into solution, the quicker the absorption and onset of clinical effects. The development of fast dissolving tablets also provides line extension in the market place.^1-4

To avoid such problems the fast dissolving tablet of Promethazine thecolate was prepared with the aim to minimize nausea and vomiting also tablet of promethazine theoclate will help in rapid and complete absorption in the gastrointestinal tract in order to achieve therapeutic success.

 MATERIALS:

Promethazine Thecolate (PMT) was obtained as a gift sample from Cipla, Baddi, India. Ac-disol, Sodium starch Glycolate, Crospovidone and Avicel PH 102 were purchased from Signet Chemicals, Mumbai, India. Dextrose, Talc and Magnesium Stearate were purchased from Loba Chemie, Mumbai. All other chemicals used were of analytical grade.

 Methods:

Preparation of Fast Dissolving Tablets of PMT:

The tablets were prepared by Superdisintegrants using single punch tablet machine (Cadmach, Ahmedabad) to produce flat faced tablets weighing 100 mg each with a diameter of 5 mm. A minimum of 50 tablets were prepared for each batch. Before compression tablet blends were evaluated for mass-volume relationship (bulk density, tapped density, Hausner’s ratio, compressibility index) and flow properties (Angle of repose).

The superdisintegrants (Ac-Di-Sol, Sodium starch glycolate and Crospovidone) in varying concentration (2-4% w/w) were used to develop the tablets. All the ingredients were shown in Table 1 were passed through sieve no. 60 and were co-grounded in a glass pestle motor ^3-5.

TABLE 1: FORMULATION OF DRUG FREE TABLETS WITH SUPERDISINTEGRANTS

*- Physical Mixture, # Microwaved, $ Lyophilized

 Pre-compression Characterization:

The quality of tablet, once formulated by rule, is generally dictated by the quality of physicochemical properties of blends. There are many formulations and process variables involved in mixing steps and all these can affect the characteristics of blend produced. The characterization parameters for evaluating the flow property of mixed blends includes bulk density, tapped density, hausner’s ratio, compressibility index and angle of repose. The characterized parameters are shown in Table 4.

Bulk density:

Apparent bulk density (ρ_b) was determined by pouring the blend into a graduated cylinder. The bulk volume (V_b) and weight of powder (M) was determined ^6-9. The bulk density was calculated using the formula

Tapped density:

The measuring cylinder containing a known mass of blend was tapped 100 times using density apparatus. The constant minimum volume (V_t) occupied in the cylinder after tappings and the weight (M) of the blend was measured ^6-9. The tapped density (ρ_t) was calculated using the formula.

Compressibility index:

The simplest way for measurement of flow of the powder is its compressibility, an indication of the ease with which a material can be induced to flow ^6-9. It is expressed as compressibility index (I) which can be calculated as follows in Table 2.

where, ρ_t = Tapped density;     ρ_b = Bulk density

TABLE 2: COMPRESSIBILITY INDEX FOR POWDER FLOW PROPERTIES

Hausner’s Ratio:

Hausner’s ratio (HR) is an indirect index of ease of powder flow. It is calculated by the following formula in Table 3.

where, ρ_t is tapped density and ρ_b is bulk density.

Lower Hausner’s ratio (<1.25) indicates better flow properties than higher ones^10-12.

 Angle of Repose:

Angle of Repose was determined using funnel method. The blend was poured through a funnel that can be raised vertically until a specified cone height (h) was obtained. Radius of the heap (r) was measured and angle of repose (θ) was calculated using the formula^10-12

;             Therefore;

where, θ is angle of repose; h is height of cone; r is radius of cone.

 TABLE 3: ANGLE OF REPOSE FOR POWDER FLOW PROPERTIES

TABLE 4: CHARACTERIZATION OF TABLETS BLENDS

 Post-compression Characterization:

After compression of powder blends, the prepared tablets were evaluated for organoleptic characteristics like color, odor, taste, diameter, thickness and physical characteristics like hardness, friability, disintegration time, wetting time, dispersion time. The results are shown in Table 6.

 General appearance:

The general appearance of a tablet, its visual identification and over all ‘elegance’ is essential for consumer acceptance. This includes tablet’s size, shape, color, presence or absence of an odor, taste, surface texture, physical flaws etc ¹³.

 Tablet thickness:

Ten tablets were taken and their thickness was recorded using micrometer (Mityato, Japan).

 Weight variation:

The weight variation test would be satisfactory method of determining the drug content uniformity. As per USP ¹⁴, twenty tablets were taken and weighted individually, calculating the average weight, and comparing the individual tablet weights to the average. The average weight of one tablet was calculated.

 TABLE 5: WEIGHT VARIATION LIMITS FOR TABLETS AS PER USP

 Hardness:

Hardness of tablet is defined as the force applied across the diameter of the tablet in order to break the tablet. The resistance of the tablet to chipping, abrasion or breakage under condition of storage transformation and handling before usage depends on its hardness. Hardness of the tablet of each formulation was determined using Pfizer Hardness Tester ¹³.

 Friability:

Friability of the tablets was determined using Roche friabilator. This device subjects the tablets to the combined effect of abrasions and shock in a plastic chamber revolving at 25 rpm and dropping the tablets at a height of 6 inch in each revolution. Preweighed sample of tablets was placed in the friabilator and were subjected to 100 revolutions. Tablets were dedusted using a soft muslin cloth and reweighed. The friability (F %) is determined by the formula.

Where, W₀ is initial weight of the tablets before the test and W is the weight of the tablets after test^{13, 16}.

 Wetting time:

Wetting time of the tablets was measured using a piece of tissue paper (12 cm X 10.75 cm) folded twice, placed in a small petridish (ID = 6.5 cm) containing 6 ml of Sorenson’s buffer (pH 6.8). A tablet was put on the paper, and the time for the complete wetting was measured ^17-19. Fig. 1 shows the wetting property.

FIG. 1: IN VITRO WETTING PROPERTY

 In vitro dispersion time:

In vitro dispersion time was measured by dropping a tablet in a glass cylinder containing 6 ml of Sorenson’s buffer (pH 6.8). Six tablets from each formulation were randomly selected and in vitro dispersion time was performed^{18, 20}.

                    FIG. 2: IN VITRO DISPERSION PROPERTY

 Disintegration test:

Disintegration of fast disintegrating tablets is achieved in the mouth owing to the action of saliva, however amount of saliva in the mouth is limited and no tablet disintegration test was found in USP and IP to simulate in vivo conditions ^28-31. A modified method was used to determine disintegration time of the tablets. A cylindrical vessel was used in which 10 mesh screen was placed in such way that only 2 ml of disintegrating or dissolution medium would be placed below the sieve (Fig.3).

To determine disintegration time, 6 ml of Sorenson’s buffer (pH 6.8), was placed inside the vessel in such way that 4 ml of the media was below the sieve and 2 ml above the sieve. Tablet was placed on the sieve and the whole assembly was then placed on a shaker. The time at which all the particles pass through the sieve was taken as a disintegration time of the tablet. Six tablets were chosen randomly from the composite samples and the average value was determined ¹⁵.

FIG. 3: DISINTEGRATION TEST APPARATUS

TABLE 6: POST-COMPRESSION CHARACTERIZATION

Optimization of Fast Dissolving Tablet:

Full factorial design:

To know the actual amount of 2 superdisintegrant for the desirable property of fast dissolving tablets a 3² randomized full factorial design was used. In this design 2 factors are evaluated, each at 3 levels and experimental trials are performed at all 9 possible combinations ^{23, 24}. The amount of SSG (X₁) and the amount of crospovidone (X₂) was selected as independent variables. The disintegration time and percentage friability were selected as dependent variables. A statistical model incorporating interactive and polynomial terms was used to evaluate the responses.

Y = b₀ + b₁X₁ + b₂X₂ + b₁₁X₁X₁ + b₂₂X₂X₂ + b₁₂X₁X₂                                                  

Where, Y is the dependent variable, b₀ is the arithmetic mean response of the 9 runs, and b₁ is the estimated coefficient for the factor X₁. The main effects (X₁ and X₂) represent the average result of changing 1 factor at a time from its low to high value. The interaction terms (X₁X₂) show how the response changes when 2 factors are simultaneously changed. The polynomial terms (X₁X₁ and X₂X₂) are included to investigate nonlinearity.

Preparation of fast dissolving tablets factorial design batches

The raw materials were passed through a no. 100 screen prior to mixing. Promethazine Thecolate, SSG, crospovidone, microcrystalline cellulose and lactose were mixed using a glass mortar and pestle. The blends were lubricated with 2% w/w talc and 2% w/w magnesium stearate. The blends ready for compression were converted into tablets using a single-punch tablet machine (Cadmach, Ahmedabad, India). The composition of the factorial design batches is shown in Table 7 respectively.

TABLE 7:  3² FULL FACTORIAL DESIGN LAYOUT (LYOPHILIZED)

X1 indicates amount of SSG (mg); X2, amount of Crospovidone (mg); DT, disintegration time; and F, friability. PCP used as checks point and optimized batch. (n=6). Fig.4 and 5 are the response surface plots.

FIG. 4: RESPONSE SURFACE FOR DISINTEGRATION TIME

FIG. 5: RESPONSE SURFACE FOR PERCENT FRIABILITY

Optimization of the fast dissolving tablet:

The fitted equation was generated relating the responses disintegration time and percentage friability to the transformed factor. The polynomial equations can be used to draw conclusions after considering the magnitude of coefficient and the mathematical sign it carries (ie, positive or negative) Table 8.

TABLE 8: SUMMARY OF RESULTS OF REGRESSION ANALYSIS

After application of full factorial design and with help of polynomial terms the optimized tablet was produced which have targeted to the disintegration time 30s and 0.5% percent friability. The optimization was done with the help of software Design Expert 7.1.6. The optimized amount of the co-processed SSG and crospovidone was incorporated in the tablet formulation (OPT) which was also used as the check point of the regression analysis model. The response surface prediction plots were formulated with the help of the software³².

TABLE 9: CALCULATIONS FOR TESTING THE MODEL IN PORTIONS

DF indicates: degrees of freedom; SS, sum of squares; MS, mean of squares;

F, fischer's ratio; R², regression coefficient.

FIG. 8: RESPONSE SURFACE FOR OPTIMIZED FORMULATION

TABLE 10: OPTIMIZATION OF FAST DISSOLVING TABLET

 Development of Optimized of Fast Dissolving Tablet:

The optimized fast dissolving tablet was prepared with the best amount of co-processed superdisintegrant suggested by the software. The prepared tablets were evaluated for its physiochemical properties ³³.  Formulation table is shown in Table 11.

 Content uniformity:

Ten randomly selected tablets were weighed and average weight was calculated, the tablets were powdered in a glass mortar pestle. The weight equivalent to 150 mg Promethazine theolate was weighed. The weighed amount was dissolved in 100 ml of Sorenson’s buffer (pH 6.8) and the solution was filtered. An aliquot of 1.0 ml from this solution was diluted appropriately with Sorenson’s buffer (pH 6.8) in separate volumetric flask. The content in each formulation was determined spectrophotometrically at 259 nm ³⁴.

 In vitro dissolution study:

In vitro dissolution study for optimized tablet and marketed tablet were carried out using USP paddle method at 50 rpm in 900 ml of Sorenson’s buffer (pH 6.8) as dissolution media, maintained at 37±0.5^o. 5 ml of aliquot was withdrawn at the specified time intervals (1 minute), filtered through whatmann filter paper and assayed spectorphotometrically at 259 nm. An equal volume of fresh medium, prewarmed at 37^o, was replaced into the dissolution media after each sampling to maintain the constant volume throughout the study ³⁵.

The various kinetic treatments were applied to the dissolution data. The in vitro dissolution data obtained were subjected to a zero order and first order kinetics to understand the release profile and release mechanism. When a graph of the cumulative percentage drug released from the tablet against time was plotted, zero order release was observed and the plot obtained was found to be linear, indicating that the release rate is independent of concentration. The rate of release of the drug can be described mathematically shown in Table 12.

Rate of release = (dCs/t) = k

Where, Cs = concentration of the drug present in the matrix,

K = rate constant,

t = time and Cs is a constant.

The amount of drug released (X) can be described as,

dx / dt = k. Integration of the equation yields

X = k t + constant

A plot of x versus t results in a straight line with the slope = k. The value of k indicated the amount of the drug released per unit of time and the intercept of the line at time zero is equal to the constant in the equation^{25, 26}.

 TABLE 12: DISSOLUTION RELEASE PROFILE OF OPTIMIZED FAST DISSOLVING TABLET

FIG. 9: COMPARISON OF ZERO ORDER RELEASE PROFILE

 TABLE 13: DISSOLUTION RELEASE PROFILE OF OPTIMIZED FAST DISSOLVING TABLET

FIG. 10: COMPARISON OF FIRST ORDER RELEASE PROFILE

TABLE 14: FIT OF VARIOUS KINETIC MODELS FOR TABLETS OF PMT       

RESULTS AND DISCUSSION:

The Fast dissolving tablets of Promethazine Thecolate were successfully prepared by direct compression technique, initially twelve formulations with varying quantity of Superdisintegrants (sodium starch Glycolate, Crospovidone and Ac-di-sol) were prepared.  Among all formulations F12 showed the best results with DT 52 Seconds and Friability 0.612%, on the basis of results this batch was further selected for optimization. The pre-compression characterization of mixed blends was done for determination of mass volume relationship and flow properties. The results of bulk density, tapped density, Hausner’s ratio, compressibility index and angle of repose indicated good compressibility and flow characteristics of the formulated mixed blends.

Further using 3² factorial design totals nine formulations were prepared by lyophilized technique. Using polynomial equation the effect of independent variables X1 (SSG) and X2 (CP) on dependent variables Y1 (DT) and Y2 (friability) was checked. The desirability of the models was found very near to one, so, these models can be used to navigate the design space. The amount of independent variables was calculated for DT 30 s, friability 0.5% and 90% drug release after 5 min. The optimized amount of independent variables was obtained easily by software and these amounts were incorporated in the check point batches. The optimized tablets were prepared and evaluated for physiochemical properties. The results indicated that the formulation satisfied all the criteria of the fast dissolving tablet.

 CONCLUSION: Optimization of fast-dissolving tablet formulation of promethazine theoclate using 32 factorial design was achieved in this study. The experimental design provided a better understanding of the effect of formulation variables on the quality of fast dissolving tablets containing the drug. Thus, by adopting a systematic formulation approach, an optimum point can be reached in the shortest time with minimal efforts.

REFERENCES:

1. Habib W, Khankari R and Hontz J: Fast dissolving drug delivery systems: critical review in therapeutics. Drug Carrier Systems 2000; 17(1): 61-72.
2. Chang R, Guo X, Burnside BA and Couch R: Fast-dissolving tablets. Pharm Tech 2000; 24(6): 52-58.
3. Dobetti L. Fast-melting tablets: developments and technologies. Pharm Tech 2001; (Suppl.), 44-50.
4. Seager H. Drug-deliver products and the zydis fast-dissolving dosage form. J Pharm Pharmacol 1998; 50: 375-382.
5. Lalla JK and Sharma AH. Fast dissolving tablet: an update. Indian Drugs 1994; 31(11): 503-505.
6. Kuchekar BS, Bhise SB and Arumugam V: Design of fast dissolving tablets. Indian J Pharm Educ 2001; 35:150.
7. Kuchekar BS, Atul, Badhan C and Mahajan HS: Mouth dissolving tablets: a novel drug delivery system. Pharma Times 2003; 35:7-9.
8. Bogner R and Meghan F. Fast dissolving tablets. US Pharmacist 2005; 27:03
9. Mishra DN, Vijaya KSG. Rapidly disintegrating oral tablets of meloxicam. Indian Drugs 2006, 43(2); 117-121.
10. Bi YX, Sunda Y, Yonezawa Yand Danjo K: Evaluation of rapidly disintegrating tablets prepared by a direct compression method. Drug Dev Ind Pharm 1999; 25 (5); 571-581.
11. Sreenivas SA, Gadad AP, Dandagi PM, Mastiholimath VS, Patil MB. Formulation and evaluation of ondeanesetron hydrochloride directly compressed mouth disintegrating tablets. Indian Drugs 2006; 43(1): 35-38.
12. Zhao N and Augsburger LL: Functionally compression of 3 classes of superdisintegrants in promoting aspirin tablet disintegration and dissolution. AAPS Pharm Sci Tech 2005; 6(4): 634-640.
13. Kuchekar BS, Mahajan HS and Bandhan AC: Mouth dissolve tablets of salbutamol sulphate: a novel drug delivery system. Indian Drugs 2004; 41(10): 592-598.
14. Khan S, Kataria P, Nakhat P and Yeole P: Taste masking of ondansetron hydrochloride by polymer carrier system and formulation of rapid-disintegrating tablets. AAPS Pharm Sci Tech 2007; 8(2): E1-E7.
15. Sunada H, Bi Y. Preparation, evaluation and optimization of rapidly disintegrating tablets. Powder Technology 2002; 122: 188-198.
16. Marshall K, Compression and consolidation of powdered solid. In: Lachman L, Liberman HA and Kaning JL, Eds., The Theory and Practice of Industrial Pharmacy, 3^rd, Varghese publishing house, Mumbai, 1987; 66-99.
17. Gorman EA, Rhodes CT and Rudnic EM. An evaluation of croscarmellose as a tablet disintegrant in direct compression systems. Drug Dev Ind Pharm 1982; 8(4): 397–410.
18. Chaudhari PD, Chaudhari SP, Kolhe SR, Dave KV and More DM. Formulation and evaluation of fast dissolving tablets of famotidine. Indian Drugs 2005; 42(10): 641-649.
19. Lindberg N, Palsoson M, Pihl A, Freeman R, Zetzener H and Enstad G. Flowability measurements of pharmaceutical powder mixtures with poor flow using five different techniques. Drug Dev Ind Pharm 2004; 30(7): 785-791.
20. Cooper J, Gunn C. Powder flow and compaction. In: Carter SJ, Eds., Tutorial Pharmacy, 3^rd, CBS publishers and distributors, New Delhi, 1986; 211-233.
21. Banker SB, Anderson NR, Tablets. In: Lachman L, Liberman HA and Kaning JL, Eds., The Theory and Practice of Industrial Pharmacy, 3^rd, Varghese publishing house, Mumbai, 1987; 293-345.
22. United States Pharmacopoeia 30/ NF25. The Official Compendia of Standards. Electronic edition. Rockville, MD: United States Pharmacopoeial Convention Inc. 2007.
23. Late SG, Yi-Ying Y and Banga AK. Effect of disintegration promoting agent, lubricants and moisture treatment on optimized fast disintegrating tablets. Int. J Pharm 2009; 365: 4-11.
24. Pandey PV, Amarnath R. Formulation and evaluation of chlorquine phosphate tablets using some disintegrants. The Indian Pharmacist 2007; 6(66): 75-79.
25. Bi Y, Sunada H, Yonezawa Y, Danjo K, Otsuka A and Lida K. Preparation and evaluation of a compressed tablet rapidly disintegrating in oral cavity. Chem Pharm Bull 1996; 44: 2121-2127.
26. Simone S, Peter CS. Fast dispersible ibuprofen tablets. Eur J Pharm Sci 2002; 15(3); 295-305.
27. Fukani J, Yonemochi E, Yoshihashi Y, Terada K. Evalution of rapidly disintegrating tablets containing glycine and carboxy methyl cellulose. Int J Pharm 2006; 310: 101-109.
28. Kuno Y, Kojima M, Ando S and Nakagami H. Evaluation of rapidly disintegrating tablets manufactured by phase transition of sugar alcohols. J. Control Release 2005; 105: 16-22.
29. Gohel MC, Parikh RK, Brahmbhatt BK and Shah AR. Preparation and assessment of novel coprocessed superdisintegratnt consisting of crospovidone and sodium starch glycolate. AAPS Pharm Sci Tech 2007; 8(1): Article 9.
30. Jeong SH and Park K. Development of sustained release fast-disintegrating tablets using various polymer-coated ion-exchange resin complexes. Int J Pharm 2008; 353; 195–204.
31. Bolton, Pharmaceutical Statistics, first ed., Marcel Decker Inc., New York, 1990.
32. M. Franz, J.E. Browne and A.R. Lewis: Experiment design, modeling and optimization strategies for product and process development, in: H.A. Liberman, M.M. 33. Reiger, G.S. Banker (Eds.), Pharmaceutical Dosage Forms: Disperse Systems, Marcel Dekker Inc., New York, 1988, pp. 427-519.
33. Costa P, Lobo JMS. Modeling and Comparison of Dissolution Profile. Eur J Pharm Biopharm 2001; 43; 123-133.
34. Polli JE, Rekhi GS, Augsburger LL and Shah VP: Methods to Compare Dissolution Profiles and a Rationale for Wide Dissolution Specification for Metoprolol Tartrate Tablets. J Pharm Sci 1997; 86; 690-700.
    

    ---

    How to cite this article:

    Hardenia SS and Darwhekar GN: Development and Optimization of Fast Dissolving Tablets of Promethazine Theoclate Using 3² Full Factorial Design. Int J Pharm Sci Res 2016; 7(6): 2499-09.doi: 10.13040/IJPSR.0975-8232.7(6).2499-09.

    ---

    All © 2013 are reserved by International Journal of Pharmaceutical Sciences and Research. This Journal licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 3.0 Unported License.

    ---