1. INTRODUCTION:

To be absorbed from the gastrointestinal tract, the oral solid dose form must dissolve. Water-insoluble drugs have poor dissolving rates and absorption characteristics, which are major concern for the pharmaceutical industry ¹. Liquisolid compacts have recently emerged as a potential approach for enhancing the dissolution rate of poorly soluble drugs². The notion of “liquisolid systems” as defined by Spireas et al. i.e Simple physical blending with selected excipients termed the carrier and coating material can be utilised to transform a liquid into a free flowing, readily compressible, and apparently dry powder³.

The drug's wetting properties and surface area that is available for dissolution are considerably improved by the liquisolid compact. Water-insoluble compounds in liquisolid compacts are likely to have increased drug dissolution, resulting in improved bioavailability⁴. The liquisolid compact approach has been successfully used to improve the in vitro release of poorly soluble drugs such as indomethacin,⁵ piroxicam,⁶ griseoful¬vin,⁷ ezetimibe,⁸ repaglinide,⁹ prednisolone,¹ etc. The liquisolid approach has been successfully used to improve the release of low dose, poorly soluble drugs. However, one of this technology's limitations is the conceptualization of a high-dose poorly soluble drug¹⁰. In order to enhance drug loading, the powder must retain high amount of liquid. However, this may result in poor flow and compression characteristics of the powder. A large amount of carrier and coating component should be used to maintain good flow and compression properties. As a result, increasing the capacity for liquid adsorption with carrier and coating component such as Neusilin could be a potential approach to loading a high dose of water insoluble drug. Neusilin US2 is an amorphous synthetic form of magnesium aluminometa silicate¹¹.

Carbamazepine (CBZ) has been used for over 40 years to treat epilepsy and trigeminal neuralgia. Carbamazepine is taken in doses of 100-200mg once or twice daily. It has a 72-96% oral bioavailability. It is practically insoluble in water. CBZ oral absorption in humans is slow, erratic, and unpredictable due to slow dissolution. One of the most major issues with this drug is its very low solubility in biological fluids, which results in poor bioavailability after oral administration. Many trials have been conducted in order to improve CBZ bioavailability. The use of water-soluble salts and polymorphic forms, the formation of water-soluble molecular complexes, Amorphisation of drug¹², Micronization¹³, Solid dispersion¹⁴, Co-grinding¹⁵, Self-emulsifying drug delivery system¹⁶, Nanosuspension¹⁷, Hot melt extrusion¹⁸, Adsorption of drugs to hydrophilic silica aerogels¹⁹, Lyophilization, microencapsulation, and Inclusion Complexation^20,21 are some of the most important formulation tools. Apart from that, this method of liquisolid compact formulation is one of the method for increasing the rate of dissolution of poorly soluble drugs²². Superdisintegrants are the most common excipients used in tablet formulations to speed up disintegration in the gastrointestinal environment and thus increase active ingredient release. Disintegration is a critical step in drug release and absorption into the systemic circulation, resulting in pharmacological effects. However, the number of available superdisintegrants is still limited, necessitating the development of more efficient ones. The addition of Starch Glutamate, a hydrophilic amino acid, to the starch may improve its ability to disintegrate. The prepared formulation was characterised and compared to marked formulations (Mazetol)²³.

2. MATERIALS AND METHODS:

2.1. MATERIALS:

CBZ was received as gift sample from Abbott Healthcare Pvt. Ltd. Mumbai and chemicals were obtained from Loba Chem in Mumbai.

2.2. METHODS:

2.2.1. Synthesis of novel superdisintegrant:

To make a starch slurry, 10 parts potato starch were accurately weighed and dispersed in 25 parts distilled water. Weighing and dissolving 10 parts glutamic acid in distilled water, it was added to the starch slurry. The dispersion was conditioned for 16 hours after adjusting the pH to 3.5 with 10ml sodium hydroxide to complete the reaction between potato starch and glutamic acid. The dispersion was washed to remove unreacted glutamic acid after conditioning, and the solid mass was dried at 60°C to yield starch glutamate. To get consistent sized particles, the dried starch glutamate was sieved with a #120 sieve and kept in desiccators²⁴.

2.2.2. Characterization of novel superdisintegrant:

2.2.2.1. Fourier transformed infrared spectrometer (FTIR):

The molecular substitution of starch glutamate was evaluated using a Fourier Transform Infrared Spectrometer (FTIR). The IR spectrum of starch glutamate was measured using an ATR Fourier Transform Infrared Spectrophotometer (Shimadzu, Japan, IRAFFINITY-1Miracal 10). A small amount of sample was taken and directly put on the ATR diamond. The sample was pressurized using a pressure arm. The spectrum was then scanned in the wavelength range of 4000-400cm^-1 ²³.

2.2.3. Solubility studies:

Saturation solubility studies in four different non-volatile solvents, namely PG (propylene glycol), PEG 200, PEG 400, and Tween 20, were needed to identify the appropriate non-volatile solvent for making liquid medication. Excess amount of carbamazepine was mixed separately with four non-volatile solvents. For 48 hours, the mixtures were shaken on an orbital shaker using the shake flask method. The solutions were then filtered through Whatman filter paper to obtain clear solutions. These filtered solutions were often diluted with 1% SLS (sodium lauryl sulphate) and their drug content was determined using UV spectrophotometry at 285 nm. To calculate carbamazepine solubility, three determinations were performed for each sample²².

2.2.4. Determination Value:

The flow properties of powder excipients (Neusilin US2) in liquid vehicles were assessed using the "angle of slide" measurement. Several homogeneous liquid vehicle/powder admixtures containing 10 g of carrier or coating ingredients and increasing volumes of liquid vehicle were prepared (PEG 200). The created powder admixtures were placed on polished metal plates, which were gradually tilted until the powder admixture was about to slide, to measure the angle of slide. The angle of slide (ø) was used to describe the angle formed between the plate and the horizontal surface. The flow properties of excipients will be altered due to adsorption of the liquid vehicle. The flowable liquid-retention potential (ф-value) of each liquid/powder admixture was evaluated using the following equation.

Ф value = liquid weight/solid weight

The graph were plotted against ф -values versus the corresponding angle of slide (ø). The flowable liquid retention potential, ф -value, of its powder, which is required for the preparation of liquisolid tablets, was represented by an angle of slide (for optimal flow properties) corresponding to 330 of a liquid/powder admixture. All measurements were taken in triplicate²⁵.

2.2.5. Liquisolid system preparation:

The amount of excipients is determined by their ф-values and liquid load factors. In the current research, neusilin was used as a carrier and coating material. The liquid load factor (Lf) is calculated using the formula below

Lf = ф + ø (1/R)……………………………………... (1)

Lf =W/Q …………………………………………….. (2)

R=Q/q ………………………………………………. (3)

Where, Ф and ø are the values of the carrier and the coating powders respectively, while R is excipient ratio¹.

In PEG 200, CBZ was suspended, as indicated in the table no. 3, and a total of 12 batches were formulated, as indicated in the Table No.1.

2.2.5.1. Preparation of CBZ liquisolid compact:

The carbamazepine, carrier and coating material, and other excipients in a liquisolid powder mixture were immediately compacted on a single punch tablet machine to yield tablets with the specified diameter, thickness, and hardness²².

Table No.1 Formulation of Liquisolid Compact of Carbamazepine

Name of superdisintegrant	Batch code	%CD	LF (mg)	R (mg)	W (mg)	Q (mg)	q (mg)	Superdisintegrnat (mg) 3%,5%, 7%	Total Weight (mg)
Crospovidone	NCP1	50%	1	20	200	200	10	3%-15.3	525.3mg
	NCP2	50%	1	20	200	200	10	5%-25.5	535.5mg
	NCP3	50%	1	20	200	200	10	7%-35.7	545.7mg
Crosscarmallose Sodium	NCS1	50%	1	20	200	200	10	3%-15.3	525.3mg
	NCS2	50%	1	20	200	200	10	5%-25.5	535.5mg
	NCS3	50%	1	20	200	200	10	7%-35.7	545.7mg
Starch Glutamate	NSG1	50%	1	20	200	200	10	3%-15.3	525.3mg
	NSG2	50%	1	20	200	200	10	5%-25.5	535.5mg
	NSG3	50%	1	20	200	200	10	7%-35.7	545.7mg
Starch Glutamate+ Crosscarmallose sodium	NSC1	50%	1	20	200	200	10	3%-15.3	525.3mg
	NSC2	50%	1	20	200	200	10	5%-25.5	535.5mg
	NSC3	50%	1	20	200	200	10	7%-35.7	545.7mg

% Cd= drug Concentration in non-volatile solvent, Lf=liquid load factor,

R= Excipient ratio, W= weight of non-volatile solvent, Q= Carrier, q= coating material.

2.2.6. Liquisolid Compact Evaluation:

2.2.6.1. Tablets' physical parameters:

In triplicate, tablets were tested for weight variation, uniformity of tablet thickness and diameter, friability, and hardness^{26; 27}.

2.2.6.2. Drug content:

The uniformity of drug content was determined as per IP 1996. The tablets were weighed and powered, and 100mg of drug powder was weighed and transferred to a 100ml volumetric flask containing 60ml of ethanol (95%). To dissolve the drug, the flask was shaken, and the volume was adjusted with ethanol. By using ethanol, 10mL of this solution was diluted to 100mL, and the absorbance of resulting solution at λmax of 285nm was measured ²⁸.

2.2.6.3. Disintegration test:

In a suitable vessel, preferably a 1000ml beaker, the assembly was submerged in liquid medium (ED-2L, Electrolab, Mumbai). The liquid volume must be such that the wire mesh is at least 25 mm below the liquid's surface and at least 25mm above the bottom of the beaker at its highest point. A thermostatic arrangement was made for heating the liquid and maintaining the temperature at 37±2℃. The assembly was submerged in a beaker containing 900ml of distilled water, and the apparatus was operate for the duration specified. The tablet's disintegration time was also recorded. Finally, the assembly was taken out from the liquid²⁸.

2.2.6.4. Dissolution studies:

The dissolution test was used to compare carbamazepine release from liquisolid tablets and mazetol, a marketed tablet. The USP Apparatus 2 (Electrolab, TDT-06L) was used in conjunction with 900ml of 1% sodium lauryl sulphate solution (1 % SLS) at 37±0.5℃, and rotated at 75rpm. After the specified time intervals, a one millilitre sample was withdrawn, and the sink condition was maintained. The samples were filtered, diluted appropriately, and spectrophotometrically analysed at 285 nm wavelength²⁹.

2.2.6.5. IR- spectroscopy (FTIR):

IR spectrum of Carbamazepine, PEG200, NeusilinUS2 and optimized formulations NSC1 were recorded using an ATR Fourier Transform Infrared Spectrophotometer (MIRacle 10)²².

2.2.6.6. Statistical analysis:

To determine whether there was a notable difference in the time required for 100% release of carbamazepine from different formulations and the marketed tablet, a one-way ANOVA with Turkey's multi comparison test was used.

3. RESULT AND DISCUSSION:

3.1. FTIR of carbamazepine

Fig No.1 FTIR Spectrum of Carbamazepine

The FTIR spectra of CBZ showed a characteristic peak at 3467.38 cm^-1 (-NH₂ vibration), 1677.77cm^-1(-C═O vibration), 1606.41cm^-1(-C═C vibration).

3.2. Characterization of novel superdisintegrant:

3.2.1. FTIR:

Fig.No.2 FTIR of Starch Glutamate

The FTIR spectrum of starch glutamate revealed a distinct peak at 1637.27cm^-1(-R-COO-R′ vibration).

3.3. Solubility studies:

Solubility of carbamazepine in propylene glycol, PEG 200, PEG 400, glycerine and Tween 20 is given in table no.2. Carbamazepine was most soluble in PEG 200 (107.94 mg/ml) and least soluble in Tween 20 (6.84 mg/ml). This is due to the dispersion of a larger fraction of drug in PEG 200, which helps to enhance drug dissolution.

Table No.2 Solubility Data of Carbamazepine

Nonvolatile Solvent	Solubility (mg/ml)
Propylene Glycol	45.10±0.16
PEG 400	68.12±0.29
PEG 200	107.94±0.62
Tween 20	6.84±0.11

3.4. Determination of (ф) value:

Relation between angle of slide of carrier and coating material in PEG 200 and corresponding ф values is depicted in Fig no.3.

Fig No.3 Liquid Retentions Potential (Ф) of Carrier and Coating Material

3.5. Liquisolid compact evaluation:

3.5.1. Physical parameters of liquisolid compact:

All the physical parameters of liquisolid compact are shown in table no 3. Liquisolid compact containing Neusilin as carrier and coating component showed good compatability, due to its high specific surface area and porosity. Thickness of liquisolid compacts were ranged from 5.33±0.02 to 5.4±0.06557mm and diameter of all the liquisolid compacts was to be in the range of 10±0 to 10.03±0.05744mm as indicated in table no 3. Thickness and diameter of tablet measured by using Vernier caliper.

Tablet hardness test were measured using Monsanto Hardness tester Hardness of tablets was found to be in the range of 3.133±0.05774kg to 3.177±0.04933kg as shown in table no 4.

Due to identical compression force, uniform hardness was achieved.

Tablets were prepared using direct compression method. Because the material was free flowing, uniform weight tablets were obtained as a result of uniform die fill. Tablets were obtained in the 10% acceptable weight variation range as specified by Pharmacopeia. The results are summarizes in table no 3.

Friability of liquisolid compact found to be 0.5129±0.0090 to 0.6003±0.01682% indicated in table no 3. As stated by USP if conventional compressed tablets that loss less than 0.5% to 1% of their weight is generally regarded as acceptable.

Table No. 3 Physical Parameters of Carbamazepine Liquisolid Compact

Formulation Code	Thickness (mm)	Diameter (mm)	Hardness (kg)	Weight Variation (mg)	Friability %
NCP1	5.4±0.06557	10.03±0.05744	3.17±0.0435	524.9±0.5967	0.5335±0.0205
NCP2	5.35±0.03512	10.03±0.05744	3.133±0.05774	533.8±0.4404	0.5129±0.0090
NCP3	5.4±0.01	10.03±0.05744	3.143±0.0589	544.1±0.4318	0.5458±0.0194
NCS1	5.37±0.03	10±0	3.17±0.0435	574.8±0.4894	0.5591±0.02171
NCS2	5.393±0.02082	10.03±0.05744	3.133±0.05774	587.9±0.3426	0.5716±0.0177
NCS3	5.34±0.02646	10±0	3.177±0.04933	600.5±0.4894	0.5514±0.01322
NSG1	5.383±0.01528	10±0	3.173±0.04619	523.9±0.4286	0.5877±0.02307
NSG2	5.383±0.02517	10±0	3.177±0.04933	534.2±0.3712	0.6003±0.01682
NSG3	5.33±0.02	10.03±0.057444	3.173±0.04619	543.2±0.3401	0.5919±0.02657
NSC1	5.427±0.07024	10.03±0.05744	3.2±0.1	577.4±0.9787	0.5312±0.01649
NSC2	5.367±0.04041	10.03±0.05744	3.177±0.06807	587±0.4648	0.5244±0.0203
NSC3	5.37±0.0435	10.03±0.05744	3.15±0.05196	600.6±0.4686	0.553±0.02453

All values are expressed as mean ± SD (n=3).

3.6. Disintegration time:

Neusilin-crosspovidone batches were failed to disintegrate. Batch NSC1 shows fast disintegration i.e. 42.5±0.5774sec. Starch Glutamate batches shows fast disintegration as compare to crosspovidone batches. Disintegration time of liquisolid compact tablets is given in table no 5 and complies as per IP specifications for all formulated batches except formulations containing Neusilin-Neusilin crosspovidone and these batches were failed to disintegrate. Crosspovidone fails to disintegrate Neusilin-Neusilin compact, for disintegration of this compact addition of 10% fujicalin necessary but it shows more disintegration time. Novel superdisintegrant starch glutamate successfully disintegrate Neusilin-Neusilin compact. Hence Liquisolid compact of Neusilin-Neusilin-starch glutamate-coroscarmellose sodium exhibited fast disintegration.

3.7. Drug content:

The requirement for a steady dose of drug between individual tablets is an essential quality attribute for all pharmaceutical formulations. Uniform drug content was observed for all the formulations given in table no 4. Which is as per the IP specification.

Table No 4. Evaluation of Carbamazepine Liquisolid Formulations

Formulation code	*Disintegration Time (sec.)**	% Drug Content
NCP1	No Disintegration	80.81±0.4494
NCP2	No Disintegration	79.87±0.2728
NCP3	No Disintegration	81.3±0.7435
NCS1	91.2±0.05774	94.23±0.4494
NCS2	85.3±0.05774	94.46±0.7784
NCS3	85.2±0.05774	95.11±0.6438
NSG1	71.4±0.05774	95.35±1.61
NSG2	74.4±0.05774	95.35±0.7435
NSG3	78.3±0.1528	96.8±1.189
NSC1	42.5±0.5774	98.8±1.189
NSC2	63.7±0.1	97.04±0.3717
NSC3	60.7±1.155	97.23±0.4494

All data is presented as mean ± SD (n=3).

3.8. Dissolution studies:

The results of in vitro percentage amount of drugs are released at varied intervals of time which is plotted against time to obtain the release profiles and are given in fig no 4.

Fig No 4. (A) Dissolution profiles of all batches of liquisolid compact and marketed formulation

Fig No 4. (B) Dissolution profiles of optimized batches of liquisolid compact and marketed Formulation

Neusilin-crosspovidone showed drug release 80.78±0.5225 to 82.27±1.7121% at the end of 60 minutes. Neusilin-Starch Glutamate, Croscarmellose sodium batch showed drug release 92.27±0.460 to 94.81±0.201% at the end of 60 minutes (shown in table no. 5). Formulations prepared with a novel superdisintegrant demonstrated higher drug release than crosspovidone batches and marketed tablets. As the concentration of crosspovidone increases drug release also increases. Crosspovidone disintegrant failed to disintegrate liquisolid compact, but a novel superdisintegrant did, and that batch had an 85% drug release rate. Starch Glutamate showed greater drug release than the marketed formulation. At the end of 60 minutes, the marketed formulation had a drug release rate of 86±0.190%. In Neusilin-Starch glutamate, Croscarmellose sodium batches NSC1 batch shows marked increase drug release than other two NSC2, NSC3 batches.

The fact that the novel superdisintegrant and the drug are already in PEG 200 while being carried by the powder particles may account for the increased dissolve rates of liquisolid compacts when compared to marketed tablet. As a result of the quick disintegration and increased wettability and surface availability to the dissolution liquid, its release is expedited. One of the hypothesised methods for explaining the increased dissolving rate from liquisolid compacts is the compacts' wettability by the dissolution media. PEG reduces the interfacial tension between the dissolution media and the tablet surface, allowing drug particles to wet more easily.

Table No 5. Percentage Amount of Drug Release of Liquisolid Compact

Time

%CDR

(Min.)

NCS1

NCS2

NCS3

NSG1

NSG2

NSG3

NSC1

NSC2

NSC3

Mazetol

35.42±

0.4996

36.58±

0.999

37.1±

0.556

35.54±

0.999

36.63±

0.0999

36.17±

0.995

31.15±

0.915

30.06±

0.993

31.85±

0.1731

33.17±

1.130

41.44±

1.044

42.32±

0.875

43.66±

1.117

48.93±

1.964

49.51±

0.9591

47.25±

0.996

44.26±

0.807

42.92±

0.870

44.38±

0.9216

44.16±

0.345

53.44±

1.096

54.9±

0.979

54.85±

0.891

53.49±

1.088

55.11±

1.271

55.56±

0.991

57.07±

0.466

55.85±

1.723

55.63±

1.947

57.08±

0.523

62.39±

0.096

59.87±

0.8834

63.34±

0.2567

63.42±

1.362

62.97±

0.997

63.88±

0.697

69.96±

0.236

71.85±

0.6351

70.71±

2.058

66.45±

0.156

65.33±

1.467

65.34±

0.4066

66.81±

0.2581

67.17±

0.8298

66.43±

0.956

64.87±

0.984

77.79±

0.343

79.05±

0.113

77.67±

1.714

72.13±

0.347

69.38±

0.2671

74.23±

0.428

69.83±

0.177

72.78±

0.3209

69.74±±

0.956

72.72±

0.986

83.52±

0.550

82.42±

0.965

82.6±

1.144

75.41±

0.583

73.28±

0.1788

75.21±

0.2835

73.73±

0.33646

76.53±

0.9379

77.67±

0.247

76.41±

0.219

87.5±

0.454

87.55±

0.368

87.67±

0.5245

81.3±

0.762

76.56±

0.09445

77.93±

0.9728

77.07±

0.2701

79.83±

0.4464

81.44±

0.134

78.72±

0.264

91.32±

0.527

90.96±

0.5372

91.14±

1.364

83.87±

0.206

80.78±

0.5225

81.12±0.6438

82.27±

1.7121

85.04±

0.8721

85.08±

0.974

85.32±

0.969

94.81±

0.201

92.67±

0.1041

92.27±

0.460

86±

0.190

All values expressed as mean ± SD (n=3).

3.9. IR- spectroscopy:

Fig No.5 FTIR Spectrum of Optimized Formulation

The continuous several range of CBZ 3470- 1600cm^-1 and 1619.29cm^-1represent the ammonia and ester group respectively present in the batch NSC1.

However, comparison of the spectra demonstrated no new characteristic peaks in the liquisolid compact formulation which indicated no physical or chemical interaction between CBZ and Starch Glutamate are given in Fig No. 5.

3.10. Statistical analysis:

There was no significant difference (P< 0.05) between the release profiles of the marketed tablet and liquisolid compacts, according to the results of a one-way ANOVA with Turkey's multi comparison test.

4. CONCLUSION:

The results indicated that, liquisolid compacts of CBZ can be prepared using a novel superdisintegrant such as Starch Glutamate. To ensure the safety of newly developed superdisintegrants, the base of synthesis was an endogen amino acid (Glutamic acid), and starch was successfully derivatized with Glutamic acid. The comparison of Starch Glutamate, Croscarmellose Sodium, and Crosspovidone-made tablets revealed that starch Glutamate and Croscarmellose Sodium-made tablets had better disintegration and dissolution behaviours than the others. It was necessary to pick superdisintegrants to maximise drug dissolving in a time when formulators were confronted with a growing number of poorly soluble drugs. The effects of Starch Glutamate, Croscarmellose Sodium, and Crosspovidone on the dissolution rates of poorly soluble drugs were investigated, and it was discovered that Starch Glutamate, Croscarmellose Sodium has the fastest dissolving rate. The drug release of a Liquisolid compact formulation with Starch Glutamate superdisintegrant was higher than that of other disintegrants and marketed tablets. This study came to the conclusion that Starch Glutamate might be used as a new superdisintegrant in the pharmaceutical industries.

5. ACKNOWLEDGEMENT:

Authors are grateful to Abbott Healthcare Pvt. Ltd, Mumbai and Gangwal Chemicals Pvt. Ltd., Mumbai for providing gift sample of drug and excipients. Also, authors are thankful to Yashoda Technical Campus, Satara and Dr. Babasaheb Ambedkar technological University, Lonere for providing research facilities.

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Received on 23.09.2021 Modified on 08.12.2021

Asian J. Res. Pharm. Sci. 2022; 12(2):107-114.

DOI: 10.52711/2231-5659.2022.00018