Effect of Various Super Disintegrants on the Drug Release Profile of Orally Disintegrating Tablets

S. Kumara Swamy¹*, G. Arun¹, Bethi Srinivas¹, Agaiah Goud B²

¹Department of Pharmaceutics, Talla Padmavathi College of Pharmacy Orus, Kareemabad, Warangal, Telangana, India

²Department of Pharmaceutics, S.R.R. College of Pharmaceutical Sciences, Valbhapur, Elkathurthy, Karimnagar-505 476, Telangana, India.

*Corresponding Author E-mail: kumar4koty@gmail.com

Received on 03.03.2016 Accepted on 28.03.2016

Asian J. Pharm. Tech. 2016; 6(2): 99-105.

DOI: 10.5958/2231-5713.2016.00014.3

ABSTRACT:

Pharmaceutical technologists have developed a novel oral dosage form which disintegrate rapidly in saliva, usually in a matter of seconds, without the need to take it water. The novel orally disintegrating tablet dosage form is used to improve patient convenience and compliance for administration of various therapeutic agents. Propranolol is metabolized in the liver during its first passage through the systemic circulation and has about 25% of the oral bioavailability. The aim of the present study was to develop and optimize orally disintegrating tablets of propranolol hydrochloride by using super disintegrants to give quick onset of action by rapidly disintegrating in a few seconds. Tablets were prepared by direct compression method using flat face 8mm size punch and evaluated hardness, thickness, weight variation, friability, drug content and dissolution tests and all the tests results are found to be within the pharmacopoeial limits. The drug release was rapid in formulation containing crospovidone as super disintegrants, followed by croscaramellose sodium and sodium starch glycolate. Crospovidone super disintegrants concentration in 15mg or 6% is suitable for the formulation of oral disintegrate tablets of Propranolol Hydrochloride.

KEY WORDS: Orally disintegrating tablets, Super disintegrants, crospovidone, Propranolol HCl

INTRODUCTION:

ODTs are solid dosage forms containing medicinal substances which disintegrate rapidly, usually in a matter of seconds, when placed on the tongue. As we know tablets and capsules have been the most popular dosage forms, one important drawback of these dosage form for patients, is the difficulty to swallow. Drinking water plays an important role in swallowing of oral dosage forms. Orally disintegrating tablets are those when put on tongue, disintegrates instantaneously releasing the drug, which dissolves in saliva^1-4.

OBJECTIVE OF THE STUDY:

Propranolol (1-(isopropylamino)- 3-(1-naphthyloxy)-2-propanol) is a nonselective beta-adrenergic blocker that interacts with β1 and β2 receptors of the autonomic nervous system with equal affinity. It lacks intrinsic sympathomimetic activity (negative inotrophic effect) and does not block α−adrenergic receptors. Propranolol hydrochloride is a stable, white, crystalline solid which is readily soluble in water and ethanol. Propranolol is a highly lipophilic substance and is almost completely absorbed following oral administration. However, most of the drug is metabolized in the liver during its first passage through the portal circulation; on average, about 25% reach the systemic circulation.

Propranolol is extensively metabolized to 4- hydroxyl-propranolol followed by conjugation with glucoronic acid⁶¹. The elimination half- life (t_1/2) of propranolol has been reported to range from between 3 hours to 6 hours or approximately 3.9 hours⁵.

Propranolol has a large volume of distribution (4 L/kg) and readily enters the CNS. Approximately, 90% of the drug is bound to plasma proteins. The drug is used in the treatment of hypertension, hyperthyroidism, cirrhosis, angina pectoris, migraine and glaucoma. The adverse effects of propranolol are bronchoconstriction and disturbance in metabolism⁶.

The aim of the present study was to develop and optimize orally disintegrating tablets of propranolol hydrochloride by using SSG, CCS and CP as super disintegrants and sweeteners sodium saccharin to give quick onset of action by rapidly disintegrating in a few seconds without the need of water with better patient compliance.

MATERIALS AND METHODS:

Propranolol hydrochloride was a gift from Dr. Reddy’s Labs, Hyderabad, India. Microcrystalline cellulose (MCC), Sodium starch glycolate (SSG), croscarmellose sodium (CCS) and crospovidone were obtained from Laksmi Chemicals Pvt. Ltd, Hyderabad. Sodium saccharine (Nutrasweet, Vadodara, Gujarat) and aerosil (S. D. Fine Chemicals, Mumbai) were
purchased and all other ingredients used in this study are either analytical grade or pharmaceutical grade.

Preformulationstudies^7-10

Preformulation studies are the first step in the rational development of dosage form of a drug substance. The objectives of preformulation studies are to develop a portfolio of information about the drug substance, so that this information is useful to develop formulation. Preformulation studies were done to investigate physical and chemical properties of drug substance alone and when combined with excipients. Preformulation investigations are designed to identify those physicochemical properties and excipients that may influence the formulation design, method of manufacture and pharmacokinetic - biopharmaceutical properties of the resulting product.

The following preformulation studies were performed in Propranolol Hydrochloride and other excipients.

1. Determination of melting point of Propranolol Hydrochloride

2. Drug-excipient compatibility studies

Melting Point:

Melting point of Propranolol Hydrochloride was determined by taking a pinch of the drug into a capillary tube, closed at one end. It was then placed in an electrically operated melting point apparatus and the temperature at which the drug melted was noted, as the melting point of the drug, Propranolol Hydrochloride.

Drug-Excipient compatibility studies:

The objective of the study was to determine the compatibility of drug with commonly employed excipients. The physical compatibility of drug substance with various excipients was carried out with an aim to select suitable excipients for a stable and robust formulation. A blend of the drug with the excipients in the suitable ratio as used in the formulation was filled in double lined poly bags and exposed to 40°C/75% RH. They were observed for any physical change against control samples kept at room temperature.

Formulation development of orally disintegrating tablets of Propranolol Hydrochloride

Propranolol Hydrochloride orodispersible tablets were prepared by direct compression method according to formula given in the table 1. A total number of nine formulations were prepared. All the ingredients were passed through 60-mesh sieve separately and collected. The drug and microcrystalline cellulose were mixed in small portion of both at each time and blended to get a uniform mixture and kept aside. Then the other ingredients were weighed and mixed in geometrical order and the tablets were compressed using flat face 8mm size punch to get a tablets of 250 mg weight using rotary tablet compress machine (Riddhi pharma machenary Ltd, 6 station mini tablet press, Ahmadabad, India). Before tablets preparation, the mixture blends of all the formulation were subjected for compatibility studies and pre-compression parameters.

Table 1: Formulation design of Propranolol Hydrochloride orally disintegrating tablets

Ingredients (mg)	F1	F2	F3	F4	F5	F6	F7	F8	F9
Propranolol Hydrochloride	40	40	40	40	40	40	40	40	40
Sodium starch glycolate	5	10	15	--	--	--	--	--	--
Croscaramellose sodium	--	--	--	5	10	15	--	--	--
Crospovidone	--	--	--	--	--	--	5	10	15
Micro crystalline cellulose	195	190	185	195	190	185	195	190	185
Sodium Saccharine	5	5	5	5	5	5	5	5	5
Talc	2.5	2.5	2.5	2.5	2.5	2.5	2.5	2.5	2.5
Magnesium stearate	2.5	2.5	2.5	2.5	2.5	2.5	2.5	2.5	2.5
Total	250	250	250	250	250	250	250	250	250

Post compression parameters^11-18

General Appearance and Organoleptic Properties

The control of a general appearance of a tablet involves the measurement of a number of attributes such as a tablet’s size, shape, color, presence or absence of an odor, taste, surface texture, physical flaws and consistency and legibility of any identifying markings.

Thickness

Thickness was determined for 20 pre weighed tablets of each batch using a digital vernier scale and the average thickness was determined in mm. Average of three readings were taken and the results were tabulated.

Weight Variation

20 tablets were selected randomly from a batch and were individually weighed and then the average weight was calculated. The tablets meet the USP specifications if not more than 2 tablets are outside the percentage limit and if no tablet differs by more than 2 times the percentage limits (table.2).

Table.2: Percentage deviations allowed for the tablets

Average weight of tablet (mg)	% deviation allowed
130 or less	10
From 130 to 324	7.5
> 324	5

Hardness Test

Prepared tablets were evaluated for their hardness by using Pfizer hardness tester. Scale was adjusted to zero; load was gradually increased until the tablet fractured. The value of the load at that point gives a measure of hardness of the tablet. Hardness was expressed in Kg/cm². Triplicate readings were taken and average was computed.

Percentage Friability

In friability testing the tablets are subjected to abrasion and shock. It gives an indication of the tablets ability to resist chipping and abrasion during transportation and shipping.

If the tablet weight is ≥ 650 mg 10 tablets were taken and initial weight was noted. The tablets were rotate in the Roche friabilator for 100 revolutions at 25 rpm. The tablets were deducted and reweighed. For conventional tablets the percentage friability should be less than 1% whereas friability values of up to 4% are acceptable for oral disintegrating and chewable tablets.

The percentage friability is expressed as the loss of weight and is calculated by the formula:

(Initial weight of tablets - Final weight of tablets)

% Friability = ______________________________________ ×100

Initial weight of tablets

Content Uniformity:

The content uniformity test is used to ensure that every tablet contains the amount of drug substance intended with little variation among tablets within a batch.

Five tablets were selected randomly and average weight was calculated. Tablets were crushed in a mortar and accurately weighed and the amount of average tablet was taken from the crushed blend. Then, the samples were transferred to three 100 ml volumetric flasks and were diluted up to the mark 6.8 phosphate buffer solution. The content was shaken periodically and kept for 24 hours for dissolution of drug completely. The mixtures were filtered and appropriate dilutions were made. The drug content in each tablet was estimated at lmax 288 nm against blank reference.

Disintegration Time:

Disintegration time is the time taken by the tablet to break into smaller particles. The disintegration test is carried out in an apparatus containing a basket rack assembly with six glass tubes which consists of a 10 mesh sieve. The basket is raised and lowered 28-32 times per minute in the medium of 900 ml of purified water which is maintained at 37±2^oC. Six tablets were placed in each of the tubes and the time required for complete passage of tablet fragments through the sieve (# 10) was considered as the disintegration time of the tablet. The time for disintegration of ODTs is generally <1min and actual disintegration time that patience can experience ranges from 5 to 60s.

Wetting Time

Wetting time of dosage form is related with the contact angle. Wetting time of the mouth dissolving tablets is another important parameter, which needs to be assessed to give an insight into the disintegration properties of the tablets; a lower wetting time implies a quicker disintegration of the tablet. The wetting time of the tablet can be measured using a simple procedure.

Method:

Five circular tissue papers of 10cm diameter were placed in a petri dish with a 10cm diameter. 10ml of water was added to petri dish and 2 drops of eosin red dye was added. A tablet was carefully placed on the surface of the tissue paper. The time required for water to reach upper surface of the tablet was noted as wetting time.

Water absorption ratio (R):

The weight of the tablet before keeping in the petri dish was noted (W_b). The wetted tablet from the petri dish was taken and reweighed (W_a) using the same. The water absorption ratio, R, was determined according to the following equation:

R = 100 (Wa - W_b) / W_b

Where W_band W_aare the weight before and after water absorption respectively

Table.3. Observation for physical compatibility tests

S.No	Name of the Excipient	Category	Ratio API: Excipient	At 40⁰c / 75%RH (30 days)
1	Propranolol Hydrochloride –API	Drug	NA	NCC
2	API + Micro crystalline cellulose	Direct compresable agent	1:1	NCC
3	API+Sodium starch glycolate	Super disintegrant	1:1	NCC
4	API+Cross Povidone	Super disintegrant	1:1	NCC
5	API+Cross Carmellose Sodium	Super disintegrant	1:1	NCC
6	API+Sodium saccharine	Sweetner	1:1	NCC
7	API+Talc	Glidant	1:1	NCC
8	API+Magnesium stearate	Lubricant	1:1	NCC

NCC: No Colour Change ; API: Active Pharmaceutical Ingredient; NA: Not Applicable

Table. 4: Evaluation of post compression parameters of formulations

Formulation code	Weight Variation (mg)	Thickness (mm)	Hardness(kg/cm²)	Friability (%)
F₁	252±2.64	3.15±0.04	3.52±0.34	0.65
F₂	252.66±1.15	3.15±0.035	3.33±0.38	0.59
F₃	249.33±3.05	3.17±0.02	3.53±0.06	0.64
F₄	252.66±3.78	3.14±0.034	3.23±0.47	0.45
F₅	251±1.52	3.17±0.026	3.52±0.23	0.49
F₆	250.33±4.16	3.15±0.011	3.37±0.25	0.56
F₇	251.33±2.51	3.13±0.037	3.52±0.28	0.66
F₈	250.33±4.04	3.16±0.025	3.37±0.49	0.64
F₉	250.33±1.15	3.16±0.04	3.55±0.23	0.52

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

Dissolution studies:

Dissolution is a process by which the disintegrated solid solute enters the solution. The test determines the time required for a definite percentage of the drug in a tablet to dissolve under specified conditions.

In-vitro drug release studies were carried out by using USP XXIII dissolution apparatus II (paddle type) at 50 rpm. The drug release profile was studied in 900 ml of 6.8 phosphate buffer maintained at 37 ± 0.5^oC. Aliquots of 5 ml of dissolution medium were withdrawn at specific time intervals (5, 10, 15, 20, 25 and 30minutes) filtered and the amount of drug released was determined by UV-Visible spectrophotometer. 5 ml of fresh 6.8 phosphate buffer was replaced as soon as the drug samples were withdrawn.The cumulative percentage of drug released was determined using UV visible spectrophotometer at 288 nm.

Preformulation studies:

Melting Point:

Melting point of Propranolol Hydrochloride was determined by capillary tube method and it was found to be 163°C. This value is same as that of the literature citation.

Drug – Excipient Compatibility Studies:

Physical compatibility studies:

The physical compatibility evaluation was performed on visual basis. The study implies that the drug and other excipients were physically compatible with each other as there was no change of physical description (Table.3).

General appearance and organoleptic properties

All the batches of MDTs of Propranolol Hydrochloride were evaluated for their organoleptic properties such as taste, colour and odour as per the procedure described in methodology section (Table 4).

Shape and thickness

Macroscopic examination of the tablets from each formulation showed circular shape with no cracks. The thickness of three tablets selected randomly was measured using vernier callipers (Table 4).

Weight variation test

All the formulations passed weight variation test as the % weight variation was within the pharmacopoeia limits of ± 10%. It was found to be from 249.33 ± 3.05 to 252.66 ± 3.78 mg. None of the formulations were exceeding the limit ± 10% specified by IP. Thus all the formulations were found to comply with the IP standard (Table 4).

Hardness and friability of the tablets:

The hardness of all the formulations was checked using tablet hardness tester, by the method described in methodology section. The average hardness of all the batches is in the range of 3.23 ± 0.47 to 3.55 ± 0.23 kg/m². The lower standard deviation values indicated that the hardness of all the formulations were almost uniform in specific method and possess good mechanical strength with sufficient hardness. The hardness of all formulations was found to be in acceptable range, because these formulations are meant to be disintegrated or dispersed on tongue between fifteen seconds to three minutes, so excessive hardens is not favored for them.

Table. 5: Evaluation of Propranolol Hydrochloride ODTs by using superdisintegrants

Formulation code	Drug content(%)	Wetting Time (sec)	Water absorption ratio(%)	Disintegration time (sec)
F₁	99.56	63.67 ±0.58	63.68 ±1.20	34.67±1.15
F₂	99.25	61.67 ±1.53	61.63 ±2.79	32 ±1.73
F₃	98.46	58.67 ±0.58	64.35 ±0.64	31.67 ±2.52
F₄	101.25	64.67 ±1.53	63.63 ±1.02	40. 0 ±3.61
F₅	99.95	61.33 ±2.08	62.33 ±2.45	37.67 ±1.53
F₆	100.35	60.33 ±1.53	64.33 ±0.67	31.33 ±1.53
F₇	98.95	63.67 ±2.52	62.13 ±3.16	32.0 ±2.65
F₈	99.56	61.33 ±2.08	61.46 ±3.12	33.33 ±2.08
F₉	100.05	59.33 ±2.08	64.31 ±1.19	31.33 ±0.58

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

The friability test is designed to evaluate the ability of the tablet to withstand abrasion in packaging, handling and shipping. A number of tablets were weighed and placed in tumbling apparatus where they were exposed to rolling and repeated shocks resulting from freefalls within the apparatus. The percentage friability for all the formulations lies in the range of 0.52 % to 0.66 %, which was found to be in limit (i.e. < 1%) (Table 4).

Estimation of drug content:

All the formulations were evaluated for the drug content estimation in a pooled sample of tablets using the procedure described in methodology section. The drug content values for all the formulations are in the range of 98.46 to 101.25% (Table 5).

Wetting Time:

Wetting is closely related to inner structure of tablets. The wetting time in different formulations vary according to the ability of superdisintegrants for swelling and capacity of absorption of water. The wetting times of the formulations were in the range 58.67 ± 0.58 to 64.67 ± 1.53seconds (Table 5).

Water Absorption Ratio:

Water absorption ratio ranged from 61.46 ± 3.12 to 64.35 ± 0.64 %. Water absorption ratio ‘R’ increased with an increase in superdisintegrants concentrations from 5-15mg. The increase in ‘R’ might be due to increase in uptake of water for crospovidone and crosscarmilose sodium at higher concentrations.

Crosspovidone and croscarmellose sodium perform their disintegrating action by wicking through capillary action and fibrous structure, respectively with minimum gelling. The relative ability of the various disintegrants to wick water into the tablets was studied. Tablets containing combination of crospovidone (F₉) quickly wicks water and were hydrated ((Table 5).

In-vitro Disintegration time:

The most important parameter that needs to be optimized in the development of orally disintegrating tablets is the disintegration time of tablets. The average in-vitro disintegration time for all the formulations lies within the range of 31.33 ± 0.58 to 40. 0 ± 3.61 seconds, that fulfilling the official requirements (< 3 minutes) for orally disintegrating tablets.

Formulations F₁, F₂, F₃ containing sodium starch gylcolate as superdisintegrant 5, 10 and 15mg concentrations and showed disintegration times at 34.67 ± 1.15, 32 ± 1.73 and 31.67 ± 2.52 seconds respectively.

Formulations F₄, F₅, F₆ containing croscarmellose sodium as superdisintegrant 5, 10 and 15mg concentrations and showed disintegration times at 40. 0 ± 3.61, 37.67 ± 1.53 and 31.33 ± 1.53 seconds respectively.

Formulations F₇, F₈, F₉ containing crospovidone as superdisintegrant 5, 10 and 15mg concentrations and showed disintegration times at 32.0 ± 2.65, 33.33 ± 2.08 and 31.33 ± 0.58 seconds respectively.

The faster disintegration of tablets containing crospovidone (F₉) may be attributed to its rapid capillary activity and pronounced hydration with little tendency to gel formation.

Thus, the results suggest that the disintegration time can be decreased by using wicking type of disintegrants. Hence the formulation F₉ showed less disintegration time when compared to all the formulations (Table 5).

In- vitro drug release studies

The in-vitro dissolution study of Propranolol Hydrochloride tablet is tested by using 6.8 phosphate buffer as dissolution medium. The in-vitro drug release study of orally-disintegrating tablets from each batch (F₁ to F₉) was carried out by using 6.8 phosphate buffer for 30 mins. The samples were withdrawn at specified time intervals and analyzed by UV-Visible Spectrophotometer. Percentage drug release was calculated on the basis of mean amount of Propranolol Hydrochloride present in the respective formulation. The percentage of drug release of orally-disintegrating formulations of Propranolol Hydrochloride was plotted against time to obtain drug release profiles.

From the in-vitro dissolution data, it was found that the formulations containing sodium starch glycolate (F₁, F₂ and F₃) showed 62.16 ± 0.45%, 77.01 ± 0.39% and 88.26 ± 0.35% drug release respectively given in the figure.1.

Tablets containing sodium starch glycolate (at 5mg, 10mg 15mg concentration) achieved more than 88.26% dissolution approximately in 30 min and met the requirements of in-vitro dissolution.

Sodium starch glycolate at a concentration of 15mg showed 88.26 ± 0.35% drug release in 30 minutes. From this data we came to know that as the concentration of SSG is increased the drug release from the formulation is increased.

From the in-vitro dissolution data, it was found that the drug release study from formulations containing croscarmellose sodium (F_4, F₅and F₆) showed 77.01± 0.25%, 86.25± 0.45% and 95.48± 0.29% drug release respectively given in the figure.2.

Tablets containing croscarmellose sodium (at 5mg, 10mg 15mg concentration) achieved more than 95.48% dissolution approximately in 30 min and met the requirements of in-vitro dissolution. Croscarmellose sodium at a concentration of 15mg showed 95.48 ±0.29% drug release in 30 minutes. From this data we came to know that as the concentration of croscarmellose is increased the drug release from the formulation is increased.

From the in-vitro dissolution data, it was found that the formulations containing crospovidone (F₇, F₈ and F₉) showed 83.36±0.32%, 96.20±0.36 % and 100.67±0.45% drug release respectively given in the figure.3.

Due to the highly porous nature and high crosslink density, crospovidone shows the super disintegrant property by both wicking and swelling action, which aids in faster disintegration of the tablet.

Due to the combined action, tablets made with crospovidone showed faster dissolution than the other superdisintegrants and 15mg showed 100.67±0.45% dissolution in 25 minutes it indicates that crospovidone was effective at concentration 15mg, by increasing concentration of crospovidone showed decreasing disintegration and dissolution time.

From this data we came to know that as the concentration of crospovidone is increased the drug release from the formulation is increased.

CONCLUSION:

In the present work, orally disintegrating tablets of Propranolol Hydrochloride were prepared by direct compression method using super disintegrants such as sodium starch glycolate, croscarmellose sodium and crospovidone.

The purpose of the present study was to develop and characterize a product of Propranolol Hydrochloride orally disintegrating tablets. Propranolol Hydrochloride tablets were prepared by direct compression technique using rotary tablet compress machine and evaluations of prepared orally disintegrating tablets were carried out with the help of different pharmacopoeial tests and found to be within the pharmacopoeial limits.

The drug release was rapid in formulation containing crospovidone as super disintegrants, followed by croscaramellose sodium and sodium starch glycolate. Crospovidone super disintegrants concentration in 15mg or 6% is suitable for the formulation of oral disintegrate tablets of Propranolol Hydrochloride.

From this data it can be concluded that formulation F₉showed better drug released and it releases 100.67±0.45% of drug in 25mins time period. Hence, formulation F₉ was selected as optimized formulation that fulfilling the official requirements for orally disintegrating tablets.

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