Fast Dissolving Tablets of Promethazine Theoclate by Using Natural Superdisintegrants

 

Shailesh Sharma*, Sudhir Bharadwaj and G. D. Gupta

 

Pharmaceutics Research Laboratory, Dept. of Pharmaceutics, ASBASJSM College of Pharmacy, Bela (Ropar) Punjab, 140111 India

.* Corresponding Author E-mail:   shaileshsharma_bela@yahoo.co.in

 

ABSTRACT

In the present study comparisons of natural and synthetic superdisintegrants were performed. Various parts of Plantago ovata such as seed powder, husk powder and isolated mucilage were prepared and used as superdisintegrants in different concentrations. Their disintegrating and physiochemical properties were evaluated and compared with synthetic superdisintegrant crospovidone. The Fast Dissolving Tablets (FDT) of promethazine theoclate (as model drug) was prepared by direct compression method using microcrystalline cellulose and sucrose as direct compressible vehicle. These tablets were evaluated for quality control tests like organoleptic characteristics, weight variation, hardness, friability,  in- vitro and in-vivo disintegration time,  in-vitro swelling time, drug content and dissolution behavior. Swelling index was also investigated with an aim to compare the swelling property of seed powder, husk powder, mucilage of Plantago ovata with crospovidone. Among all the superdisintegrants, Plantago ovata mucilage showed the highest swelling index. Hence, the present study revealed that this natural superdisintegrant (Plantago ovata mucilage) showed similar disintegrating property than the most widely used synthetic superdisintegrants in the formulations of FDT.

 

KEY WORDS     Fast dissolving tablet, Promethazine Theoclate, Plantago ovata mucilage, seed powder, husk.

 

INTRODUCTION:

Fast dissolving drug delivery is rapidly gaining acceptance as an important new drug delivery technology1.  These  dosage  forms  dissolve  or disintegrate in oral cavity within a minute even without the need of water or chewing. Usually, superdisintegrants are added to a drug formulation to facilitate the break-up or disintegration of tablet or capsule content into smaller particles that can dissolve more rapidly. Many substances like microcrystalline cellulose (MCC), crospovidone, croscarmellose sodium (Ac-Di-Sol), sodium starch glycolate (SSG) have been used  in  the  formulations  of  fast  dissolving  tablets (FDT). Similarly, various natural substances like gum karaya, modified starch and agar have been used in the formulations of FDTs as natural superdisintegrants. Natural origin is preferred over semi-synthetic and synthetic substances because they are comparatively cheaper, abundantly available, non-irritating and non- toxic in nature. Plantago ovata has gained importance as a traditional medicine throughout the world due to its best medicinal properties. Morphologically Plantago ovata is a bushy herb growing in sandy, salty soil, is believed to  be  native  to  Asia,  the  Mediterrian  Region  and  North Africa. Plantago ovata seeds have characteristic of mucilage formation  on   catching  humidity.   Plantago  ovata   have various pharmaceutical formulation characteristics like binding, disintegrating and sustaining properties2. Due to these properties it is largely used in pharmaceutical industry, food preparations, ayurvedic medicine, unani remedies, preparation of crude drugs, etc. Hence, in the present study, seed powder, husk powder and mucilage of Plantago ovata were  used  as  superdisintegrants to  develop  FDTs  of  the promethazine theoclate. The disintegration and swelling properties of FDT were compared with other widely used superdisintegrant crospovidone. Promethazine theoclate is used for the treatment of allergic symptoms. Taken before travelling, promethazine is  effective in  preventing motion sickness.   Vomiting from other causes can be treated with higher or more frequent doses. Its biological half-life (2.2 hours) is very short and its bioavailability is only 25% indicating extensive first pass metabolism in liver. In view of substantial first pass effect and its shorter plasma half-life, therefore is an ideal drug candidate for rapid release drug delivery system3.

 

MATERIALS AND METHOD:

Materials

Seeds  and  husk  of  Plantago  ovata  were  purchased from the local market of Mohali(Punjab). Promethazine theoclate was obtained as a gift sample from Mehta Chemicals, Mumbai, India. Crospovidone and microcrystalline cellulose were obtained from Signet Chemicals Mumbai, India. Other materials used in the study were of pharmaceutical grade.

 

Methods

Preparation of Seed and Husk Powder

The powder of seeds and husk were powdered by a hand automatic grinder and sieved (#80) and stored in a desiccator until use.

 

Isolation of Mucilage of Plantago ovata

The seeds of Plantago ovata were soaked in distilled water for 48 h and then boiled for few minutes so that mucilage was completely released into water. The material collected was squeezed through muslin cloth for  filtering  and  separating  out  the  marc.  Then,  an equal volume of acetone was added to the filtrate so as to  precipitate the  mucilage.  The  separated  mucilage was  dried  (in  oven  at  temperature less  than  60°C), powdered, sieved (#80) and stored in a desiccator until use.

 

Preformulation Characterization of Superdisintegrants

The superdisintegrants were evaluated for their physicochemical properties4. The particle size was characterized by using SEM studies. The particle size was calculated by microscopic method. The mass volume    relationship    and    flow    properties    were determine for their compressibility property. The swelling index is the volume in milliliters that is occupied by 1 g of drug or any substance after it has swollen in an aqueous liquid for 4 h. The method of studying swelling index for seeds, husk, mucilage of Plantago ovata and crospovidone were carried out. The physical mixture of drug with superdisintegrants was allowing standing for seven days and the assay of drug was performed for compatibility studies. The effect of superdisintegrants on the drug solubility was evaluated; the excess promethazine theoclate was placed in 10 ml of Sorenson’s Buffer (pH 6.8) in sealed glass tubes in contact with various superdisintegrants for 24 hours at 250C  on  a  khan  type  wrist  shaker.  The  saturated solution was centrifuged and the supernatant was filtered   through   0.45   µ m   Whatman   filter   paper (Whatman Ltd., Middlesex, UK) diluted suitably with sorenson’s      buffer      and      analyzed      by      UV spectrophotometer at 300 nm(model 1601, UV-Visible spectrophotometer, Shimadzu, Kyoto, Japan).

 

Preparation of Fast Dissolving Tablets

Fast dissolving tablets of promethazine theoclate were prepared by direct compression method. The drug and excipients were passed through sieve (#80) to ensure better mixing. Microcrystalline cellulose and sucrose were used as a direct compressible vehicle5. Superdisintegrant crospovidone, seed powder, husk powder and mucilage of Plantago ovata were used in different proportions (1 to 5%) as shown in Table 1. The powders were compressed using a single-punch tableting machine (Cadmach Machinery Co. Pvt. Ltd., India) equipped with 6.5 mm round, flat and plain punches.

 

Evaluation of Fast Dissolving Tablets

Quality  control  tests  for  FDTs  of  all  formulations  were performed, and the average values were calculated.

 

Sensory Evaluation

The prepared tablets were sensory evaluated for the color, odor  taste  and  for  roughness  and  irritation.  For  taste, roughness   and   irritation,   six   healthy   volunteers   were selected. They were asked to keep the tablet in the mouth without biting and without drinking water. Immediately after the sensory evaluation, volunteers were asked to rinse the mouth without ingesting disintegrating particles6.

 

Thickness and Diameter

The  thickness and  diameter of  the  prepared tablets were measured using Digital Vernier Caliper. It is expressed in mm.

 

Weight Variation

Weight variation was determined by weighing 20  tablets individually; the average weight and percent variation of tablet was calculated individually.

 

Hardness and Crushing Strength

Hardness was determined by taking ten tablets from each formulation, using a Monsanto tablet hardness tester and the average of applied pressure (kg/cm2) for crushing the tablet was determined.

 

Friability

The  friability  of  the  tablet  was  determined  by  Roche Friabilator. Initially weighed (Wo) 20 tablets after dusting and placing them in a friability tester, which was rotated for 4 min at 25 rpm. After dusting, the total remaining mass of tablets (Wf)  was  recorded  and  the  percent  friability  was calculated by

F = 100 X Wo − Wf

Wo

Tablet Porosity

The porosity of the tablet (  ) was calculated from the tablet weight (M (g)), tablet volume (V (cm3)), and thickness and true density of powders (ρ (g/cm3)) using the following equation:

                     M

ε (%) = 1 −       X 100

Vρ

Fast dissolving tablets of promethazine theoclate were                                                      

 

Figure 1 - SEM photographs: (A) Seed Powder (B) Husk Powder (C) Mucilage (D) Crospovidone

 

The diameter and thickness of tablet for calculation of tablet  volume  were  measured  with  a  micrometer. The tablet volume was calculated from the diameter and thickness. The true density of powder was determined by a pycnometer (autopycnometer type: 1320, Micromeritics, USA).

 

Disintegration Time

The  in-vitro  disintegration  time  of  the  fast  dissolving tablets was determined in accordance with officials. Disintegration test was performed using a disintegration test apparatus using sorenson’s buffer (pH 6.8) as medium7. A tablet was added to each of the six tubes of the apparatus and one disc was added to each tube. The time in seconds for complete disintegration of the tablet with no palpable mass remaining in the apparatus was measured.

 

The in-vivo disintegration time in the oral cavity of six human volunteers was measured by placing the tablet on the tongue until no lumps remain. It is also expressed in seconds8.

 

Figure 2 – Evaluation of swelling property of natural and synthetic superdisintegrants

 

Wetting time

Wetting time is closely related to the inner structure of tablets and to the hydrophilicity of the excipients. The water penetration rate into the powder bed is proportional to the pore radius. It is obvious that pore size becomes smaller and wetting time increases with an increase in compression force  or  a  decrease in  porosity.  A  linear relationship  exists  between  wetting  time  and disintegration time. Thus wetting is an important step for disintegration process to  take  place. A  piece of  tissue paper  folded  twice  was  placed  in  a  small  petridish (internal diameter = 65mm) containing 6 mL of water9. A tablet was placed on the paper and the time for complete wetting  of  the  tablet  was  measured  in  seconds.  The method was slightly modified by maintaining water at 370C.

 

Drug Content

Ten  tablets  were  powdered,  and  12.5  mg  equivalent weight of promethazine theoclate in tablet powder was accurately weighed and transferred into a 100 ml volumetric flask. Initially, 10 ml of sorenson’s buffer (pH 6.8) was added and shaken for 10 min. Then, the volume was made up to 100 ml with sorenson’s buffer (pH 6.8). Subsequently, the solution in the volumetric flask was filtered, and 1 ml of the filtrate was suitably diluted and analyzed at 250 nm using UV-visible spectrophotometer. The drug content of the sample was estimated from their calibration curve.

 

In-vitro Dissolution Study

Dissolution study was carried out by using a digital tablet dissolution test apparatus in 900 ml sorenson’s buffer (pH 6.8) at 50 rpm at 37°C. Five-millilitre aliquots were withdrawn at different time intervals. The aliquots were filtered and analyzed spectrophotometrically at 250 nm. After each sampling, equal volume of fresh medium was added to maintain a constant volume. The data thus obtained were fitted to various kinetic models and mathematically illustrated.

 

Figure   3   –   Comparative   study   of   superdisintegratns:   (A) Crospovidone (B)Seed Powder (C) Husk Powder (D) Mucilage

 

RESULT AND DISCUSSION:

Formulation scientists generally use superdisintegrants for developing  fast  disintegrating tablets  or  for  improving dissolution  of  active  pharmaceutical  ingredients  from solid dosage forms. The superdisintegrants are used from as low as 4% to as high as 66% in fast dissolving formulations.  Therefore  Preformulation characterization and   compressibility   of   the   superdisintegrant   is   an important attribute. The obtained superdisintegrants from Plantoga ovata shows good properties. The obtained disintegrants were compared with crospovidone. The mucilage showed similar properties with crospovidone at same concentration in tablet formulation.

 

Figure 4 – Correlation between in vitro and in vivo disintegration time: ● Crospovidone ○ Seed Powder ▼ Husk Powder ∆ Mucilage

 

Preformulation Characterization

The SEM photographs of superdisintegrants clear their particle  shape.  In  the  mucilage  photographs  the  pores were observed which may enhance their water absorption and  swelling properties (Fig  1).  The  particle size  was similar to the crospovidone. The average size of obtained superdisintegrants was found 189.565 to 517.692 (Table 2). Bulk density depends on the particle size, shape and tendency of particles to adhere together. It was also important in size hoppers and receivers for milling equipment and  for  size  blending equipment. The  bulk density  of  superdisintegrants  varied  between  0.61  to 1.29g/cm3. The result indicated good packaging capacity of tablets. The tapped density was found in the range of 0.82 to 1.55g/cm3. By using these two density data Hausners Ratio and Compressibility Index was calculated. If the bed of the particles is more compressible then the powder will be less flowable and vice  versa. Material having value less than 20 % termed as free flow materials.

 

The superdisintegrants had hausners ratio of 1.2 or less indicating the good flowability. The compressibility index was     found     between     6.796     to     25.610%.    The compressibility – flowability correlation data indicated a fairly good flowability of the obtained superdisintegrants. The flowability of the powder was also evidenced by the angle of repose. The angle of repose was below then 300

 

showed good to excellent flow properties of powder. Lower the friction occurring with in the mass and better flow rate. The results reveal that mucilage, husk powder and  crospovidone  exhibited  good  flow.  The  angle  of repose  of  seed  powder  was  42.379º,  showed  passable flow. Therefore, improve flow is recommended by addition of lubricants and glidants. The mucilage of Plantago ovata showed very high percentage of swelling index as compared to the other superdisintegrating agents (Fig. 2). No significant physical and chemical changes were seen in the incorporated drug after period of seven days, the  assay of  the  drug  was  near  to  cent percent, which signifies the compatibility of promethazine theoclate  with  the  obtained  and  synthetic superdisintegrant. There was no significant enhancement on apparent solubility with the  seed powder and husk powder. The solubility of the drug was increased with the addition of mucilage and crospovidone signifies an interaction on the ground mixing due to an association between the functional groups of promethazine theoclate and mucilage or crospovidone which may have occurred at the molecular level. Due to change of crystalline form of promethazine theoclate to amorphous form enhancement in the apparent solubility was observed. A change in crystalline property of promethazine theoclate was confirmed by the reduction in the melting point.

 

Figure 5 - Effect of tablet porosity on disintegration time of various superdisintegrant on different level (1-5% of tablet weight):   ● Crospovidone ○ Seed Powder ▼ Husk Powder ∆ Mucilage

 

Physical Characterization of Fast Dissolving Tablet

To develop fast dissolving tablet with the simple and low cost direct compression method, it was necessary to find suitable  excipients  with  good  compatibility, compactability and disintegrating ability. By varying the disintegrants and their concentration, twenty formulations were formulated. All tablets were prepared under similar conditions to avoid processing variables. The precompression parameters were studied. All the formulations  showed  good  mass-volume  relationship, flow properties. The results show the good compactibility of the formulations. In the sensory evaluations the tablet to be said NO DEFECT TABLET, the shape and size of the tablets were uniform without any processing problems like chipping, crowning, capping. The tablets had no odor and  good  palatability.  The  thickness  of  the  prepared tablets were found to be 3.228 to 3.319 mm. The diameter of all the tablets was found 5.012mm. The uniformity of the thickness and diameter show uniform tabletting process. Table 3 shows the formulations contains small weight variation but in limit of official acceptance. The hardness of the formulations was kept constant with in the range of 3-4 kg/cm2 to compare the disintegrating properties of different disintegrants and their varying concentration. The friability value of the formulations was not more than 0.991%. The result of friability indicates that the tablets were mechanically stable and could not handle the rigors of transportation and handling (Table 3). The in-vitro disintegration time   found  34 to 98 seconds. The in-vitro disintegration at different disintegrants and varying concentrations were showed in fig. 3. The white area of the curve describes the property of disintegration.. The in-vivo disintegration time was also found similar to in-vitro studies. The correlation coefficient between in- vitro and in-vivo were found to near one (Fig. 4).

 

Table 1 – Formulation table of fast dissolving tablet of promethazine theoclate (in mg)

Ingredients	FDT1- FDT5	FDT6- FDT10	FDT11- FDT15	FDT16 – FDT20
Promethazine Theoclate	12.5	12.5	12.5	12.5
Crospovidone	1 - 5	-	-	-
Seed Pwder	-	1 - 5	-	-
Husk Powder	-	-	1 - 5	-
Mucilage	-	-	-	1 - 5
MCC	30	30	30	30
Sucrose	25	25	25	25
Xylitol	27.5	26.5	25.5	24.5
Mg. Stereate	2	2	2	2
Talc	2	2	2	2

 

Figure 6 – Influence of porosity (%) on disintegration time at different concentration level (1-5%)

 

Influence of porosity on disintegration time

Crospovidone and various parts of seed of Plantoga ovata

are swells to a large extent in contact with water. The resulting formulations showed a minimum disintegration time, depending on their porosity and concentration of disintegrants (Fig. 5).  The disintegration time with in the 60 seconds achieved at a porosity ≈14%. (Fig. 6). The higher concentration of disintegrants disperse quickly at low porosities at the same compaction force, where as formulation containing  3-4%  of  disintegrant  lead  to  a broad range, in which tablet disintegrantion occurs with in 85 s at a acceptable compression load.

 

Influence of wetting time on tablet disintegration

The   first   step   in   the   disintegration  process  is   the penetration of water into tablet. Fig. 7 shows the relationship between  swelling time,  disintegration time and concentration of disintegrants. The results shows time required for complete wetting of tablets as function of concentration9. Water uptake increased with increase of concentration of disintegrants. Wetting is closely related to the inner structure of tablets. The water penetration rate into the powder bed is proportional to pore radius10. It is obvious that porosity becomes smaller and wetting time increases with the decrease in concentration of superdisintegrant at same compression load. Since husk powder was more porous and  flaked shaped and after compression the pores are not collapsed, on other hand the swelling capacity of crospovidone and mucilage were excellent results in good swelling index of the tablets. Seed powder particles are of a concave-convex shaped and their pores were fairy collapsed by compression process, the tortuosity of pores in seed powder tablet was greater than other, so that wetting time was prolonged to some extent.

 

Figure 7 - Effect of tablet swelling time on disintegration time of various superdisintegrant on different level (1-5% of tablet weight):

● Crospovidone ○ Seed Powder ▼ Husk Powder ∆ Mucilage

 

Chemical Characterization of Fast Dissolving Tablet

The percentage drug content of all the formulation were found to be between 97 and 108% of promethazine theoclate, which was within the acceptable limit. The cimulative percentage drug released by which each tablet in-vitro release studies was based  on the mean content of drug present in respective tablet. The in-vitro dissolution profile of prepared tablet are shown in Fig 8.

 

Table 2 - Preliminary evaluation of superdisintegrants

Parameters	Crospovidone	Seed Powder	Husk Powder	Mucilage
Particle Size (µ m)	517.692±4.509	189.565±7.226	312.393±23.501	458.281±7.898
Bulk Density (gm/cm3)	1.08±0.19	0.61±0.02	1.29±0.12	0.96±0.11
Tapped Density (gm/cm3)	1.22±0.13	0.82±0.09	1.55±0.15	1.03±0.24
Hausners Ratio	1.130	1.344	1.202	1.073
Comressibility Index (%)	11.475	25.610	16.774	6.796
Angle of Repose (o)	28.374±1.37	42.379±2.93	35.156±4.88	32.871±2.46
Swelling Index (%)	27.92±2.93	5.89±0.82	26.35±1.23	29.44±2.85

 

Table 3 Characterization of fast dissolving tablet

Formulation	Parameters
	Weight variation (mg)	Friability (%)	Disintegration time (s)	Swelling time (s)
FDT1	100.608±0.868	0.718±0.162	78.333±2.082	87.333±1.528
FDT2	100.849±0.806	0.573±0.334	67.667±1.528	76.333 ±1.528
FDT3	100.007±0.909	0.684±0.378	61.000±1.000	67.667±0.577
FDT4	100.292±0.816	0.754±0.340	51.667±1.528	56.333±3.055
FDT5	99.977±0.886	0.991±0.232	34.000±2.000	44.667±0.577
FDT6	100.180±0.929	0.838±0.136	105.6673.215	126.000±3.606
FDT7	100.650±1.219	0.588±0.314	98.000 ±2.000	110.667±8.145
FDT8	100.301±1.020	0.370±0.274	69.333 ±2.309	90.333 ±0.577
FDT9	99.416±0.682	0.336±0.143	60.333 ±0.577	82.000 ±1.000
FDT10	99.686±0.773	0.612±0.226	51.333 ±1.528	67.333 ±0.577
FDT11	100.646±1.408	0.476±0.127	96.667 ±1.528	106.667±1.528
FDT12	100.231±1.022	0.629±0.303	86.667 ±1.528	92.667 ±0.577
FDT13	100.372±1.032	0.854±0.188	66.667 ±1.155	76.333 ±1.528
FDT14	100.257±1.164	0.667±0.548	51.667 ±0.577	67.333 ±0.577
FDT15	100.145±1.358	0.558±0.298	49.667 ±1.528	57.000 ±4.583
FDT16	100.739±1.047	0.777±0.189	83.667 ±0.577	100.667±1.155
FDT17	100.120±1.424	0.663±0.054	71.333 ±1.155	81.333 ±0.577
FDT18	100.214±0.997	0.636±0.327	65.667 ±1.155	72.333 ±0.577
FDT19	100.084±1.280	0.715±0.095	55.667 ±1.528	63.333 ±0.577
FDT20	99.346±0.733	0.456±0.111	35.333 ±0.577	52.000 ±1.732

 

Table 4 - Various kinetic fit models for fast dissolving tablet of promethazine theoclate

Formulation	Cum. drug release (mg) within 5 min.	Zero Order			First Order			Hixon Crowell Equation
		Intercept	Rate constant (K) mg/hr	Linearity R2	Intercept	Rate constant (K) hr	Linearity R2	Intercept	Rate constant (K)	Linearity R2
5% Crospovidone	84.527	2.304	1.996	0.8531	1.9452	0.0693	0.9851	0.618	0.1096	0.9244
5%  Seed Powder	52.015	1.4459	1.2614	0.849	1.9507	0.0273	0.9881	0.863	0.0914	0.9199
5% Husk Powder	80.851	1.4649	1.9955	0.849	1.9458	0.0621	0.9081	0.809	0.1379	0.9553
5% Mucilage	84.479	2.0055	2.0463	0.8884	1.9608	0.0701	1.9899	0.676	0.1201	0.9462

 

Figure 8 – In vitro Dissolution Profile of fast dissolving tablet of Promethazine Theoclate

The percentage of promethazine theoclate released within 5 minute is shown in table. The dissolution study of the optimized tablets revealed rapid release of drug. The drug has to dissolve from the interface between drug and dissolution media, the maximal media uptake volume can be  taken  as  an  estimation  of  the  total  surface  area available  for  drug  dissolution to  take  place.  The  high cumulative drug release from tablet was probably due to the fibrous nature of disintegrants. Each fiber can act as a hydrophilic channel  to  facilitate  water  uptake  into  the tablet matrix and help increase the water contact area with drug.  The  release  of  drug  was  found  ≈100% after  10 minutes. The release data was co-processed and fitted to various kinetics models to know the release order. The data obtained after kinetics treatment found that the release from formulation follows first order release kinetics (Table 4). The correlation coefficients of log cumulative percent drug retained versus time were found to be much closer to one and greater than value of zero order release kinetics. The good relationship was evidenced in the     Hixon – Crowell's Cube Root Law which signifies the drug is assumed to dissolve out from matrix or from surface of the device. As the drug is released  the  distance  for  diffusion becomes  increasing greater.

 

CONCLUSIONS:

In the present study, natural and synthetic superdisintegrants differed in their ability to disintegrate promethhazine theoclate tablet into their primary particles when used in different concentration levels. Such difference can potentially affect drug dissolution rate. The fast   dissolving   tablet   developed   in   this   work   will hopefully contribute to  improve drug administration to patient’s with swallowing and chewing difficulties. These tablets are much useful in chemotherapy, PONV and motion sickness.

 

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Accepted on 09.08.2008   © RJPT All right reserved