Formulation and Evaluation of Immediate Release Pravastatin Sodium Tablets

Yamunappa¹, Ravi Kumar¹*, Pooja Shetty, Prathibha Suvarna, Narayana Swamy VB²

¹M.Pharm (Pharmaceutics), Research Scholar, Karavali College of Pharmacy, Mangalore

²Department of Pharmaceutics, Karavali College of Pharmacy, Mangalore

³Department of Pharmacognosy, Karavali College of Pharmacy, Mangalore

*Corresponding Author E-mail: ravikumar300@gmail.com

ABSTRACT:

The objective of this research was to formulate fast dissolving tablets of Pravastatin sodium that disintegrate in the oral cavity upon contact with saliva and there by improve therapeutic efficacy. Pravastatin sodium is used for the treatment of myocardial infarction. Fast dissolving tablets of pravastatin sodium were prepared by direct compression method using three different superdisintegrants-Sodium starch glycollate, Crosscarmellose sodium and Crosspovidone (2%, 4% and 6%) and three different diluents (mannitol and spray dried lactose) in different concentrations. Eighteen formulations were prepared by using different diluents and evaluated were evaluated for various pre and post compression parameters like angle of repose, bulk density, tapped density, compressibility index, Hausner’s ratio, tablet hardness, friability, weight variation, wetting time, water absorption ratio in vitro dispersion time, drug content and in vitro dissolution studies. FTIR and DSC studies revealed that there was no chemical interaction between the drug and the excipients. Formulation L6 was found to be the best on the basis of wetting time, in vitro disintegration time and in vitro drug release. The formulation L6 containing spray dried lactose as diluent and crosspovidone (6%) was found to be the optimized combination. Stability studies were carried out at 250°C±20°C/60%±5% RH and 400°C±20°C/75%±5% RH for formulation L6 for 60 days. The results of stability studies indicated no significant changes with respect to physicochemical properties, in vitro disintegration time, wetting time and in vitro drug release.

KEYWORDS: Fast dissolving tablets, Pravastatin sodium, Superdisintegrant, Direct compression, Sodium starch glycollate, Crosscarmellose sodium, Crosspovidone.

INTRODUCTION:

Many patients express difficulty in swallowing tablets and hard gelatin capsules, resulting in non-compliance and ineffective therapy¹. Difficulty in swallowing (dysphagia) is a common problem of all age groups, especially elderly and pediatrics, because of physiological changes associated with these groups of patients. In recent years, a variety of pharmaceutical research has been conducted to develop new dosage forms.

Most of the efforts have been focused on ease of medication. Recent advances in novel drug delivery systems (NDDS) aim to enhance safety and efficacy of drug molecules by formulating a convenient dosage form for administration and to achieve better patient compliance. One such approach led to development of fast dissolving tablets. Advantages of this drug delivery system include administration without water, convenience of administration and accurate dosing as compared to liquids, easy portability, ability to provide advantages of liquid medication in the form of solid preparation, ideal for pediatric and geriatric patients and rapid dissolution/absorption of the drug, which may produce rapid onset of action. Some drugs are absorbed from mouth, pharynx and oesophagus as the saliva passes down into the stomach and in such cases bioavailability of the drug is increased: pre-gastric absorption can result in improved bioavailability and as result of reduced dosage, improved clinical performance through a reduction of unwanted effects^2-7.

Pravastatin Sodium is one of a class of lipid-lowering compounds, the statins, which reduce cholesterol biosynthesis. These agents are competitive inhibitors of HMG-CoA reductase, the enzyme catalyzing the early rate-limiting step in cholesterol biosynthesis, conversion of HMG-CoA to mevalonate. The recommended starting dose is 40 mg once daily. If a daily dose of 40 mg does not achieve desired cholesterol levels, 80 mg once daily is recommended. In patients with significant renal impairment, a starting dose of 10 mg daily is recommended. It has reported to have extensive first-pass metabolism and also very low half life of 1- 1.5 hrs was selected as model drug for the study. Their absorption and bioavailability require improvement in the dissolution rate and efficiency. Immediate release tablet offers a suitable and practical approach in serving desired objective of faster disintegration and dissolution characteristics with increased bioavailability. The objective of the present study was to develop and optimize such a novel drug delivery system for Pravastatin sodium by simple and cost-effective direct compression method using different diluents and superdisintegrants combination having sufficient mechanical integrity, good content uniformity and acceptable palatability.

MATERIALS AND METHODS:

Materials:

Pravastatin was obtained as gift sample from Biocon Pharma, Bangalore, India. All other materials, excipients, solvents and reagents were either analytical or Pharmacopoeial grade and they were procured from S.D.fine Chemicals Mumbai.

Methods:

Drug- polymer interaction studies:

Fourier Transform Infra-Red (FT-IR) spectral analysis:

Fourier–Transform Infrared (FT–IR) spectrums of pure Pravastatin Sodium and combination of drug and excipients were obtained by a Fourier-Transform Infrared spectrophotometer, (FTIR-8300, Shimadzu, Japan) using the KBr disk method (2 mg sample in 200 mg KBr). The scanning range was 400 to 4000 cm^-1 and the resolution was 1cm^-1. This spectral analysis was employed to check the compatibility of drugs with the excipients used.

Differential Scanning Calorimetry (DSC) analysis:

DSC analysis was performed using Shimadzu DSC-60, Shimadzu Limited Japan. A 1:1 ratio of drug and excipient was weighed into aluminium crucible. And sample was analyzed by heating at a scanning rate of 20°C over a temperature range 40-430⁰C under nitrogen environment.

Preparation of pravastatin sodium fast dissolving tablets

Pravastatin Sodium tablets each containing 40 mg of Pravastatin Sodium were prepared by direct compression method. The different superdisintegrants used were Sodium starch glycollate, Crosscarmellose sodium and Crosspovidone in different concentrations. The diluents used were mannitol and lactose along with other excipients. The study was intended to compare the disintegration efficiency of these superdisintegrants in various concentrations (2%, 4%, and 6%) and to select the best possible diluent-superdisintegrant combination among the various diluents and superdisintegrants used.

Accurate quantities of Pravastatin Sodium, superdisintegrants (preferred superdisintegrants in different concentrations), mannitol/lactose, aspartame, talc and magnesium stearate were weighed and passed through mesh #60. All the ingredients except lubricant were thoroughly blended in a glass mortar with pestle for 15 min.

Table 1: Composition of FDT’s of Pravastatin Sodium with lactose and mannitol as diluents

Ingredients Mg/tablets)	FORMULATIONS
	L1	L2	L3	L4	L5	L6	L7	L8	L9
Pravastatin Sodium	40	40	40	40	40	40	40	40	40
Sodium Starch Glycollate	4	8	12		-	-	-	-	-
Cross-povidone	-	-	-	4	8	12	-	-	-
Cross-carmellose Sodium	-	-	-	-	-	-	4	8	12
Mannitol	146	142	138	146	142	138	146	142	138
lactose	-	-	-	-	-	-	-	-	-
Aspartame	4	4	4	4	4	4	4	4	4
Mag-nesium Stearate	2	2	2	2	2	2	2	2	2
Orange flavour	2	2	2	2	2	2	2	2	2
Talc	1	1	1	1	1	1	1	1	1
Aerosil	1	1	1	1	1	1	1	1	1
Total weight (mg)	200	200	200	200	200	200	200	200	200

Table 1: Continued

Ingredients Mg/tablets)	FORMULATIONS
	M1	M2	M3	M4	M5	M6	M7	M8	M9
Pravastatin Sodium	40	40	40	40	40	40	40	40	40
Sodium Starch Glycollate	4	8	12		-	-	-	-	-
Cross-povidone	-	-	-	4	8	12	-	-	-
Cross-carmellose Sodium	-	-	-	-	-	-	4	8	12
Mannitol	-	-	-	-	-	-	-	-	-
lactose	146	142	138	146	142	138	146	142	138
Aspar-tame	4	4	4	4	4	4	4	4	4
Mag-nesium Stearate	2	2	2	2	2	2	2	2	2
Orange flavour	2	2	2	2	2	2	2	2	2
Talc	1	1	1	1	1	1	1	1	1
Aerosil	1	1	1	1	1	1	1	1	1
Total weight (mg)	200	200	200	200	200	200	200	200	200

After sufficient mixing lubricant was added and mixed for additional 2 to 3 min. Before compression, hardness was adjusted. 10 mg of Pravastatin Sodium were compressed on 10-station rotary punching machine, each weighing 100 mg. The compositions of Pravastatin Sodium fast dissolving tablets were given in table 1.

1. Evaluation of fast dissolving tablets

i) Pre-compressional studies:

Angle of Repose (Ө):

The angle of repose of API powder was determined by the funnel method. The accurately weighed powder blend was taken in the funnel. The height of the funnel was adjusted in such a way that the tip of the funnel just touched the apex of the powder blend. The powder blend was allowed to flow through the funnel freely on to the surface. The diameter of the powder cone was measured and angle of repose was calculated using the following equation.

Ө = tan^-1 (h/r)

Where, Ө is the angle of repose, h is the height of pile and r is the radius of the base of pile.

ii) Bulk Density and Tapped density:

Loose bulk density (LBD) and tapped bulk density (TBD) of tablet blends were determined using bulk density apparatus. Tablet blend was passed through #18 sieve to break the clumps and transferred to 100ml graduated cylinder. Initial volume was observed. The cylinder was tapped initially 200 times from a distance of 14±2 mm. The tapped volume was measured to the nearest graduated unit. This was repeated for other tablet blends. The LBD and TBD were calculated in g/ml using following formula:

LBD = weight of the powder / volume of the packing

TBD = weight of the powder / tapped volume of the packing

iii) Carr’s Index:

The Compressibility Index of the powder blend was determined by Carr’s compressibility index. It is a simple test to evaluate the BD and TD of a powder and the rate at which it is packed down. The formula for Carr’s Index is as below,

Carr’s Index (%) = [(TBD-LBD) x100]/TBD

Where,

LBD = Loose Bulk Density and TBD = Tapped Bulk Density

iv) Hausner ratio:

The Hausner’s ratio is a number that is correlated to the flowability of a powder or granular material. The Hausner ratio of the powder was determined by the following equation:

Hausner ratio = TBD / LBD

a) Post-compressional studies:

i) General appearance:

The fast dissolving tablets, morphological characterization which includes size, shape, colour, presence or absence of odour, taste surface texture was determined.

ii) Thickness and diameter:

Five tablets were picked from each formulation randomly and thickness and diameter was measured individually. It is expressed in mm and standard deviation was also calculated. The tablet thickness and diameter was measured using vernier calliper.

iii) Hardness:

Hardness indicates the ability of a tablet to withstand mechanical shocks while handling. The hardness of the tablets was determined using Monsanto hardness tester. It is expressed in kg/cm². Five tablets were randomly picked and hardness of the same tablets from each formulation was determined. The mean and standard deviation values were also calculated.

iv) Friability test:

Friability test is performed to assess the effect of friction and shocks, which may often cause tablet to chip, cap or break. Roche Friabilator was used for the purpose. Pre-weighed sample of ten tablets were placed in the Friabilator, which was then operated at 25 rpm for 4 minutes or ran upto 100 revolutions. After 100 revolutions the tablets were dusted and reweighed. Compressed tablets should not lose more than 1% of their weight.

The % friability was then calculated by the following formula:

Percentage friability = (Initial weight - Final weight /Initial weight) × 100

v) Weight variation:

20 tablets were selected randomly from each formulation and weighed individually to check for weight variation. The US Pharmacopoeia allows a little variation in the weight of a tablet.

vi) Drug content uniformity:

Twenty tablets were weighed and powdered. Powder equivalent to 40 mg drug was transferred into a 100 ml volumetric flask. Volume was made with phosphate buffer pH 6.8. After few minutes the solution was filtered; rejecting first few ml of the filtrate. 10ml of filtrate was taken in a 50 ml volumetric flask and diluted up to the mark with phosphate buffer pH 6.8 and analyzed spectrophotometrically at 238 nm. The concentration of Pravastatin Sodium (in µg/ml) was calculated by using the standard calibration curve of Pravastatin Sodium.

vii) Wetting time and water absorption ratio:

A piece of tissue paper folded twice was placed in a small petridish (i.d = 6.5 cm) containing 6 ml of water. A tablet was placed on the paper and the time required for complete wetting was then measured.

The water absorption ratio, R, was determined using the following equation,

R = Wa - Wb / Wb × 100

Where,

Wb is the weight of the tablet before water absorption and

Wa is the weight of the tablet after water absorption.

viii) In vitro dispersion time:

One tablet was placed in a beaker containing 10 ml of phosphate buffer pH 6.8 at 37±0.5ºC and the time required for complete dispersion was determined.

ix) In vitro disintegration time:

In vitro disintegration time was performed by apparatus specified in USP at 50 rpm. Phosphate buffer pH 6.8, 900 ml was used as disintegration medium, and the temperature of which was maintained at 37±2°C and the time in second taken for complete disintegration of the tablet with no palpable mass remaining in the apparatus was measured in seconds.

x) In vitro drug release studies:

In vitro drug release studies were carried out using dissolution apparatus USP type XXIII at 50 rpm. The dissolution medium consisted of 900 ml of Phosphate buffer pH 6.8 maintained at 37±1⁰C. The drug release at different time intervals was measured using a double beam UV Spectrophotometer at 238 nm.

xi) Data Analysis:

Various models were tested for explaining the kinetics of drug release. To analyze the mechanism of the drug release rate kinetics of the dosage form, the obtained data were fitted into zero-order, first order, Higuchi, Korsmeyer-Peppas release model and Hixson-Crowell equation.

xii) Stability Studies:

Stability of a drug has been defined as the ability of a particular formulation, in a specific container, to remain within its physical, chemical, therapeutic and toxicological specifications.

In the present study, stability studies were carried out at 25°C±2°C/60%±5% RH and 40°C±2°/75%±5% RH for a period of 60 days for the selected formulations. The formulations were then evaluated for changes in the physicochemical properties, wetting time, in vitro disintegration time and in vitro drug release.

RESULTS AND DISCUSSION:

Drug-Excipients Compatibility Studies:

Fourier transform infrared (FTIR) analysis

Physical mixture of Pravastatin Sodium and formulative ingredients were subjected for IR spectroscopic analysis to ascertain whether there was any interaction between drug and excipients used. The IR spectras showed similar characteristic peaks at their respective wavelengths with minor differences. The similarity in the peaks indicated the compatibility of drug with formulation excipients. IR spectra of the physical mixture of drug with formulative ingredients were depicted in figure 1-2.

Figure 1: FTIR spectra of Pravastatin Sodium pure drug

Figure 2: FT-IR Spectra of Physical mixture of drug +all excipients

Differential Scanning Calorimetry:

The DSC thermograms of pure Pravastatin Sodium showed sharp melting endothermic peak at 172°C indicating crystalline nature of Pravastatin Sodium. The endothermic peak for the drug in physical mixture and formulation L6 showed minor changes in the melting endotherm of drug could be due to the mixing of drug and excipients, which lower the purity of each component in the mixture and may not necessarily indicate potential incompatibility. The result showed that drugs were compatible with excipients. DSC thermograms of drug, physical mixture of drug and excipients and formulation L6 were shown in figure 3.

Figure 3: Differential scanning thermograms of pravastatin sodium (a), physical mixture of drug and excipients (b), and L6 (c)

From the above IR Study, DSC study and physical observation it was concluded that there was no significant Drug and Excipient interaction was observed. The results of IR study shown that there was no change in drug’s peak after the preparation of tablet. And the result of DSC study indicated that there was no change in melting point of drug, when it was used along with other excipients. So we can conclude that drug and other excipients are compatible which each other.

A) PRECOMPRESSIONAL PARAMETERS:

Blended drug/excipient mixture of all the formulations were subjected for various precompressional evaluation parameters such as bulk density, tapped density, compressibility index, Hausner’s ratio and angle of repose. The angle of repose of all the formulations ranged from 24.13^o to 29.21^o. The flow properties of all the formulations exhibited good flow properties. The bulk density and tapped density for all the formulation varied in range of 0.40-0.60 gm/ml and 0.52-0.80 gm/ml. The values obtained lies within the acceptable range and with not much difference found between bulk density and tapped density. These results may further influence property such as compressibility and tablet dissolution. The percentage compressibility index and Hausner’s ratio for all the formulations lies within the acceptable range of 11.11-25.0% and 1.12-1.30. The results of precompression parameters of various formulations containing lactose and mannitol diluents were reported in table 2.

Table 2: Pre compression evaluation of Labetalol powder blend with lactose and mannitol as diluents

Formulations	Angle of Repose	Bulk Density (gm/cc)	Tapped Density (gm/cc)	Carr’s Index %	Hausner Ratio
M1	25.95	0.49	0.56	12.50	1.14
M2	25.09	0.47	0.53	11.32	1.12
M3	27.21	0.55	0.64	14.06	1.16
M4	28.88	0.46	0.52	11.53	1.13
M5	24.34	0.47	0.54	12.96	1.14
M6	24.13	0.55	0.62	11.29	1.12
M7	26.29	0.48	0.54	11.11	1.12
M8	27.59	0.47	0.53	11.32	1.12
M9	25.00	0.52	0.61	14.75	1.17
L1	26.41	0.47	0.54	12.96	1.15
L2	25.01	0.54	0.68	20.58	1.25
L3	28.33	0.55	0.72	23.61	1.30
L4	29.21	0.59	0.74	20.27	1.25
L5	26.95	0.46	0.57	19.40	1.23
L6	25.73	0.54	0.67	19.40	1.24
L7	27.54	0.57	0.74	22.97	1.29
L8	28.70	0.60	0.80	25.00	1.33
L9	25.66	0.49	0.57	14.03	1.16

*All values are expressed as mean ± SD, n=3

POST-COMPRESSIONAL PARAMETERS:

Immediate release pravastatin sodium tablets were prepared by using different superdisintegrants (sodium starch glycolate, croscarmellose sodium and crospovidone) and diluents (mannitol and lactose) with various concentrations by direct compression method.

All the tablet formulations were evaluated for parameters such as shape, colour, thickness, hardness, friability, weight variation, drug content, in vitro disintegration time, in vitro dispersion time, wetting time, water absorption ratio, in vitro dissolution studies, model fitting of release profile and stability studies.

a) General appearance:

All the fast dissolving tablets from each batch were found to be flat, white in colour, circular in shape and having good physical appearance. There was no change in the colour and odour of the tablets from all the batches.

b) Thickness and diameter:

Thickness and diameter of all prepared fast dissolving tablets was measured by using calibrated vernier callipers. Tablet thickness should be controlled within ± 0.1% variation of standard value to facilitate packaging and consumer acceptance. The tablets of all the formulations showed thickness and diameter in the range of 2.701 mm to 2.709 mm, 6.01 to 6.04 mm respectively.

c) Hardness:

Tablets require certain amount of strength, hardness to withstand mechanical shocks during manufacture, packaging and shipping. The hardness was found to be in the range of 3.0 to 4.0 kg/cm². The obtained results revealed that the tablets were having good mechanical strength and compactness.

d) Friability:

Adequate tablet hardness and resistance to friability are necessary to prevent damage to the tablet during manufacture, packing and transport. % Friability of tablets less than 1% was considered acceptable .Percent friability ranged from 0.21 to 0.55%.

e) Weight variation:

The average weight of Pravastatin Sodium fast dissolving tablet was 200mg. the weight variation was found to be in the range of 199 mg to 203 mg. The obtained results indicated that all tablets of different formulations were within the I.P specifications.

f) Mouth feel:

The prepared formulations were subjected for mouth feel. The volunteers felt good taste in all the formulations. As the drug is bitter the presence of Aspartame and orange flavour in all the formulations showed good, palatable taste.

g) pH:

pH of the solution of all the tablets was found to be between 7.1 to 7.5, which suggest that the tablets can be conveniently administered orally and will not cause any discomfort.

h) Drug content:

To evaluate a tablet’s potential for efficacy the amount of drug in the tablet need to be monitored from tablet to tablet and batch to batch. The percentage drug content was found to be in the range of 98.00% to 99.7% (table 3).

i) Wetting Time:

Wetting time is an important parameter related to water absorption ratio, which needs to be assessed to give an insight to the disintegration properties of the tablets. Wetting is closely related to the inner structure of the tablets and the hydrophilicity of the excipients. Wetting time was used as a parameter to correlate with disintegration time in oral cavity.

Table 3: Post compression evaluation of pravastatin Sodium FDT’s containing with lactose and mannitol as diluents

Formulation Code	Thickness (mm)*	Diameter (mm)*	Hardness (kg/cm^2)*	Friability (%)**	Weight variation test (mg)***	Drug Content (%)***	pH	Mouth feel
M1	2.709±0.03	6.01±0.01	3.5 ± 0.23	0.24±0.03	202.55 ± 1.17	99.78±0.28	7.2	+
M2	2.704±0.06	6.01±0.03	3.7 ± 0.25	0.27±0.01	201.00 ± 1.05	98.65±0.51	7.5	+++
M3	2.701±0.01	6.01±0.03	3.8 ± 0.23	0.35±0.03	200.05 ± 1.15	98.90±0.65	7.1	++
M4	2.702±0.04	6.03±0.02	3.7 ± 0.24	0.32±0.04	201.05 ± 1.17	99.47±0.47	7.2	+++
M5	2.703±0.01	6.02±0.02	3.4 ± 0.24	0.37±0.01	201.00 ± 1.01	98.70±0.73	7.4	+
M6	2.701±0.04	6.01±0.02	3.5 ± 0.25	0.33±0.02	203.55 ± 1.11	98.55±0.09	7.5	+++
M7	2.701±0.03	6.01±0.04	3.6 ± 0.26	0.34±0.02	199.80 ± 0.11	98.58±0.44	7.2	+
M8	2.704±0.02	6.03± 0.04	3.2 ± 0.24	0.29±0.01	202.25 ± 1.22	98.29±0.75	7.1	+++
M9	2.705 ± 0.01	6.03±0.02	3.3 ± 0.27	0.39±0.4	200.30 ± 1.12	99.30±0.56	7.4	++
L1	2.707±0.02	6.01±0.03	3.5±0.09	0.21±0.03	200.23±0.03	98.0±0.01	+	7.4
L2	2.703±0.01	6.01±0.04	3.6±0.08	0.35±0.03	201.21±0.02	99.0±0.01	+	7.5
L3	2.702±0.01	6.02±0.02	3.5±0.21	0.25±0.01	201.00±0.04	98.5±0.02	+	7.4
L4	2.701±0.03	6.01±0.02	4.0±0.11	0.30±0.06	199.25±0.05	98.0±0.01	+	7.2
L5	2.702±0.03	6.02±0.01	3.5±0.2	0.25±0.01	201.15±0.05	96.5±0.02	+	7.5
L6	2.709±0.01	6.03±0.02	3.0±0.1	0.30±0.06	199.17±0.02	98.0±0.01	+	7.2
L7	2.704±0.05	6.03±0.02	3.5±0.12	0.45±0.04	202.15±0.04	99.0±0.01	+	7.1
L8	2.705±0.01	6.01±0.01	4.0±0.16	0.55±0.02	200.16±0.01	99.5±0.05	+	7.1
L9	2.707±0.04	6.04±0.01	3.5±0.12	0.45±0.04	202.18±0.03	99.0±0.01	+	7.2

*All values are expressed as mean ± SE, n=5; **All values are expressed as mean ± SE, n=10; ***All values are expressed as mean ± SE, n=20; += Average; ++= good, +++= excellent

Figure 4: Comparison of wetting time and water absorption ratio of various formulations of Pravastatin Sodium FDT’s containing Mannitol

Figure 5: Comparison of wetting time and water absorption ratio of various formulations of Pravastatin Sodium FDT’s containing lactose

This is an important criterion for understanding the capacity of disintegrants to swell in presence of little amount of water. Since the dissolution process of a tablet depends upon the wetting followed by disintegration of the tablet, the measurement of wetting time may be used as another confirmative test for the evaluation of dispersible tablets.

It was found that formulation containing sodium starch glycollate and lactose (L1) showed maximum wetting time 71 sec. Formulation containing sodium starch glycollate and Mannitol (M1) showed wetting time 52 sec.

Formulation containing crosspovidone and mannitol (M4) showed minimum wetting time 55 sec, whereas those containing crosspovidone and lactose (L6) showed least wetting time of 15 sec. The comparison of wetting time and in vitro disintegration time of formulations containing Mannitol and lactose as diluents was depicted in figure 4 & 5 respectively. The wetting time for the optimized formulation (L6) 15 seconds indicates quicker disintegration among twenty seven formulations.

j) Water Absorption Ratio:

Water absorption ratio, which is an important criterion for understanding the capacity of disintegrants to swell in presence of little amount of water, was calculated. It was found to be in the range of 62.6 to 84.1% and 42.5 to 85.5% in formulations containing Mannitol and lactose as diluents respectively.

The Water absorption ratio increased with increase in the concentration of superdisintegrant from 2-6 %. The water absorption ratio was found to be in the increasing order. This increase was due to the water up taking ability of the superdisintegrants. More the superdisintegrant concentration greater was water absorption.

Water absorption ratios for all these formulation batches varied in the following decreasing order: Crosspovidone > Crosscarmellose sodium > Sodium starch glycollate.

k) In vitro Disintegration Time:

Disintegration, the first important step for a drug absorption from a solid dosage form after oral administration was preliminarily focused. The internal structure of tablets that is pore size distribution, water penetration into tablets and swelling of disintegration substance are suggested to be the mechanisms of disintegration. This indicates that the tablets would disintegrate almost instantaneously when they will come in contact with even slight amount of saliva in the mouth.

Disintegration time was determined as per I.P. for all the formulations. The formulations containing Mannitol as diluent showed disintegration time less than 75 seconds, formulations containing lactose as diluent showed disintegration time less than 160 seconds. Least in vitro disintegration time (19 sec) was shown by formulation containing crosspovidone and lactose (L6).

Disintegration time was observed in the order of

Crosspovidone < Crosscarmellose Sodium < Sodium Starch Glycollate.

l) In vitro Dispersion Time:

In vitro dispersion time was measured by the time taken to undergo uniform dispersion. All formulations showed rapid dispersion within seconds. Formulated fast dissolving tablets containing Mannitol as diluent showed dispersion time less than 77 seconds, Formulated fast dissolving tablets containing lactose as diluent showed dispersion time less than 167 seconds.

Figure 6: Comparison between in vitro disintegration time and in vitro dispersion time of various formulations of pravastatin Sodium FDT’s containing Mannitol

Figure 7: Comparison between in vitro disintegration time and in vitro dispersion time of various formulations of pravastatin Sodium FDT’s containing Lactose

Eighteen formulations were prepared, the optimum concentration were identified based on the in vitro dispersion time results. Based on the observation, it was concluded that formulation L6 containing 6% crospovidone with spray dried lactose was the optimized combination due to its fast in vitro dispersion time while compare with other twenty seven formulations( figure 6-7).

m) In vitro Dissolution Studies:

The in vitro drug release characteristics were studied in phosphate buffer pH 6.8 using tablet dissolution apparatus USP XXIII. The samples were withdrawn at different time intervals and analyzed at 238 nm and the cumulative percentage drug released was determined.

Mannitol as diluent

The in vitro dissolution data of formulations were shown in figure 8-10. Formulation M1, M2 and M3 released 92.2%, 93.7% and 95.3% drug respectively in 15 mins. Formulation M4, M5 and M6 released 90.96%, 93.8% and 96.4% drug respectively in 15 mins. Formulation M7, M8 and M9 released 89.8%, 92.01% and 96.1% drug respectively in 15 mins. In vitro dissolution studies revealed that the release rate of Pravastatin Sodium from fast dissolving tablet containing sodium starch glycolate (M3) was maximum i.e 95.30%

Figure 8: Comparison of dissolution profile of various formulations of Pravastatin Sodium FDT’s containing Mannitol+SSG (M1-M3)

Figure 9: Comparison of dissolution profile of various formulations of Pravastatin Sodium FDT’s containing Mannitol +CP (M4-M6)

Figure 10: Comparison of dissolution profile of various formulations of Pravastatin Sodium FDT’s containing Mannitol +CCS (M7-M9)

Lactose as diluent:

The in vitro dissolution data of formulations were shown in figure 11-13. Formulation L1, L2 and L3 released 84.8%, 89.4% and 90.8% drug respectively in 15 mins. Formulation L4, L5 and L6 released 88.2%, 93.76% and 98.5% drug respectively in 15 mins. Formulation L7, L8 and L9 released 77.1%, 89.0% and 95.1% drug respectively in 15 mins. In vitro dissolution studies revealed that the release rate of Pravastatin Sodium from fast dissolving tablet containing Crosspovidone (L6) was maximum i.e 98.5%.

Figure 11: Comparison of dissolution profile of various formulations of Pravastatin Sodium FDT’s containing Lactose+SSG (L1-L3)

Figure 12: Comparison of dissolution profile of various formulations of Pravastatin Sodium FDT’s containing Lactose+CP (L4-L6)

Figure 13: Comparison of dissolution profile of various formulations of Pravastatin Sodium FDT’s containing Lactose+CP (L7-L9)

Comparison of dissolution profile of optimized formulations with marketed product (Pravator-40mg®)

Dissolution profile of the optimized formulations (L6) was compared with the marketed formulation of pravastatin Sodium (Pravator-40mg®). From the in vitro dissolution study it revealed that optimized formulations shown similar release pattern in comparison with marketed formulation. Comparison of Dissolution profile of marketed and optimized formulation of pravastatin Sodium tablets is shown in figure 14.

Figure 14: Comparison of dissolution profiles of optimized formulations (L6) with marketed formulation (Pravator-40mg®)

n) Data Analysis:

The results of in vitro dissolution studies of optimized formulation (L6) was plotted in Zero order, First order, Higuchi and Korsmeyer-Peppas release model to study the mechanism of drug release. The optimized formulation L6 showed Higuchi Matrix which described the drug release, as a diffusion process based on the Fick’s law, square root time dependent. The result of modeling and drug release kinetics of optimized Pravastatin Sodium FDT (L6) were shown in table 4.

o) Stability Studies:

Stability studies of formulation L6 was performed at 25^°C ± 2^°C/60% ± 5% RH and 40^°C ±2^°C/75% ± 5% RH for a period up to 60 days. The formulations were selected for stability studies on the basis of their high percentage cumulative drug release and also results of in vitro disintegration time, wetting time and in vitro dispersion studies.

There was no change in colour and shape of the tablets when stored at 25^°C ±2^°C/60% ± 5% RH and 40^°C ±2^°C/75% ±5% RH and observed every 20 days interval upto 60 days. Formulation L6 showed not much variation in any parameter. From these results it was concluded that formulations were stable and retained its original properties (figure 15).

Figure 15: Cumulative % Drug released from formulation L6 stored at 40^°C ± 2^°C/ 75% ± 5% RH for different days interval

Table 4: Model fittings of release profile of optimized formulation of Pravastatin Sodium FDT’S (L6) using different models

Formulation Code	MATHEMATICAL MODELS (KINETICS)
	Zero Order	First Order	Higuchi Matrix	Peppas	Best Fit Model
L6	0.642	0.877	0.877	0.728	Higuchi matrix

CONCLUSION:

From the study conducted and from the observations and the results obtained thereof, following conclusions were drawn:

● FTIR studies concluded that drug and excipients were compatible with each other.

● The formulated tablets were satisfactory in terms of hardness, thickness, friability, weight variation, drug content, wetting time, water absorption ratio, in vitro disintegration time, in vitro dispersion time and in vitro drug release.

● Formulations containing superdisintegrant Crosspovidone showed least wetting time and in vitro disintegration time.

● As the superdisintegrant concentration increases, the wetting time and in vitro disintegration time on tablets decreases.

● Formulation L6 was found to be the best on the basis of wetting time, in vitro disintegration time and in vitro drug release.

● The formulation L6 containing lactose as diluent and crosspovidone (6%) was found to be the optimized combination.

● Stability studies of promising formulation L6 indicated that there were no significant changes in drug content, wetting time, in vitro disintegration time and in vitro dissolution studies.

ACKNOWLEDGEMENTS:

The authors are thankful to Principal and Management of Karavali College of Pharmacy, Mangalore for providing all the facilities and support for this research project. The authors are also thankful to Biocon Pharma, Bangalore, India for generous gift samples of Pravastatin.

REFERENCES:

1. Hanawa T, Watanabe A, Tsuchiya T, Ikoma R. New oral dosage form for elderly patients: preparation and characterization of silk fibroin gel. Chem Pharm Bull 1995; 43: 284-88.

2. Watanable Y, Ishikawa Y, Utoguchi N, Matsumoto M. Preparation and evaluation of tablets rapidly disintegrating in saliva containing bitter taste masked granules by the compression method. Chem. Pharm. Bull 1999; 47: 1451-57.

3. Kaushik D, Dureja H, Saini TR. Mouth dissolving tablets: A review. Indian Drugs-Bombay. 2004; 41: 187-193.

4. Seager H. Drug delivery products and the Zydis fast dissolving dosage forms. J Pharm Pharmacol 1998; 50:375-82.

5. Chang RK, Guo X, Burnside BA, Cough RA. Fast dissolving tablets. Pharm Tech 2000; 24:52-8.

6. Dobetti L. Fast-melting tablets: Developments and technologies. Pharma Tech 2001; (Suppl.):44-50.

7. Kuchekar BS, Arumugam V. Fast dissolving tablets. Indian J Pharm Educ 2001; 35:150-152.

Received on 04.04.2016 Modified on 23.04.2016

Accepted on 05.05.2016 ©A&V Publications All right reserved

Res. J. Pharm. Dosage Form. and Tech. 2016; 8(2):105-118.

DOI: 10.5958/0975-4377.2016.00014.8