FORMULATION AND EVALUATION OF FAST DISSOLVING TABLETS OF PROCHLORPERAZINE MALEATE

MATERIALS

LIST OF CHEMICALS

Category	Material	Manufacturer
Drugs	Prochloperazine Maleate	Mehta Pharmaceuticals, Mumbai
	Promethazine Theoclate	Mehta Pharmaceuticals, Mumbai
	Cisplatin IV Injection	Pfizer (Perth) Pty Ltd., Australia
Disintegrants	Croscamellose Sodium	Signet Chemicals, Mumbai
	Crospovidone	Signet Chemicals, Mumbai
	Sodium Starch Glycolate	Signet Chemicals, Mumbai
Effervescent Agents	Sodium Bi Carbonate (AR)	Central Drug House (P) Ltd., Mumbai
Effervescent Agents	Citric Acid	Central Drug House (P) Ltd., Mumbai
Sublimating Agents	Menthol	Central Drug House (P) Ltd., Mumbai
	Camphor	Central Drug House (P) Ltd., Mumbai
	Thymol	Central Drug House (P) Ltd., Mumbai
Solubility Enhancers	Β-Cyclodextrin	Signet Chemicals, Mumbai
Solubility Enhancers	PEG-4000	Central Drug House (P) Ltd., Mumbai
Diluents	Microcrystalline Cellulose (Avecil)	Signet Chemicals, Mumbai
	Sucrose	Central Drug House (P) Ltd., Mumbai
	Lactose	Central Drug House (P) Ltd., Mumbai
	Mannitol	Central Drug House (P) Ltd., Mumbai
Lubricant	Magnesium Stereate	Central Drug House (P) Ltd., Mumbai
Glidant	Talc	Central Drug House (P) Ltd., Mumbai
Buffers	Dibasic Sodium Phosphate	E.Merck (India) Ltd., Mumbai
	Monobasic Sodium Phosphate	E.Merck (India) Ltd., Mumbai
	Sodium Hydroxide	E.Merck (India) Ltd., Mumbai
Others	Methanol	S.D. Fine Chem. Ltd., Mumbai
	Acetone	S.D. Fine Chem. Ltd., Mumbai
	Amaranth Dye	Central Drug House (P) Ltd., Mumbai
	Ethyl Alcohol	S.D. Fine Chem. Ltd., Mumbai
	Dichloromethane	Central Drug House (P) Ltd., Mumbai
	Isopropyl Alcohol	S.D. Fine Chem. Ltd., Mumbai

LIST OF INSTRUMENTS AND EQUIPMENTS

S.No.	Name	Manufacturer /model
1.	Digital Weighing Balance	Shimadzu, Japan
2.	Dissolution Rate Test Apparatus	Campbell Electronics, Mumbai
3.	Friabilator	Campbell Electronics, Mumbai
4.	Hardness Tester	Scientific Engineering Co. Ltd., Delhi
5.	High Precision Water Bath	Narang Scientific Works NSW-129
6.	HPLC	Shmadzu, Japan
7.	Hot-Air Oven	Narang Scientific Works NSW-129
8.	Infra Red Spectrophotometer	Perkin Elmer 1600
9.	Melting Point Apparatus	Remi’s Equipment Pvt. Ltd.
10.	Micrometer	Mityato, Japan
11.	pH Meter	Control dynamic pH meter
12.	SEM	Hitachi S-3400, Japan
13.	Tablet Disintegration Apparatus	Campbell Electronics, Mumbai
14.	Tablet Punching Machine	Cadmach, Ahmedabad
15.	UV Spectrophotometer	Shimadzu-1700 spectrophotometer

Noise level	Within 0.0002 Abs. or less (at 700nm).
Baseline flatness	±0.002 Abs (190 to 200nm) 1h. After the light source is ON
Baseline stability	Within 0.001 Abs/h or less(700 nm)
Light source	1 h. After the light source is ON 20W Halogen lamp, Deuterium lamp.
Monochromator	Czerny-Turner spectrophotometer Uses aberration-correcting concave blazed holographic grating
Detector	Silicon Photodiode
Operating humidity	30 to 80% (15⁰ C to below 30⁰ C) 35 to 70% (30⁰ C to 35 ⁰ C)
Response	Quick, fast/medium/slow
Wavelength scanning	10, 100, 190, 260, 2000, 3000 and 6000 nm/min
Baseline Stability	± 0.001Abs./h

Technology Followed – Superdisintegrant Addition

The superdisintegrants (Ac-di-sol, sodium starch glycolate and crospovidone) in varying concentration (1-5% w/w) are used to develop the tablets. All the ingredients are shown in Table 3.1 were passed through sieve no. 60 and were co-grounded in a glass pestle motor.^25-27

Table 4.1: Formulation of drug free tablets with superdisintegrants

Ingredients (mg)	F1	F2	F3	F4	F5	F6	F7	F8	F9	F10	F11	F12	F13	F14	F15
Ac-di-sol	1	2	3	4	5	-	-	-	-	-	-	-	-	-	-
Sodium starch glycollate	-	-	-	-	-	1	2	3	4	5	-	-	-	-	-
Crospovidone	-	-	-	-	-	-	-	-	-	-	1	2	3	4	5
Avicel PH102	55	54	53	52	51	55	54	53	52	51	55	54	53	52	51
Lactopress	25	25	25	25	25	25	25	25	25	25	25	25	25	25	25
Mannitol	15	15	15	15	15	15	15	15	15	15	15	15	15	15	15
Talc	2	2	2	2	2	2	2	2	2	2	2	2	2	2	2
Magnesium stearate	2	2	2	2	2	2	2	2	2	2	2	2	2	2	2

Technology Followed - Sublimation

Another technology employed for developing fast dissolving tablets were incorporating subliming agents (camphor, thymol and menthol) in varying concentration (5-20% w/w). Ingredients shown in Table 3.2 were co-grounded in glass pestle glass mortar. The mixed blends of excipients were compressed using a single punch machine to produce flat faced tablets weighing 100 mg. Tablets were subjected for drying for 6 h under vacuum (30 kpa) at 50^o for sublimation to make tablets porous.^28-30

Table 4.2: Formulation of drug free tablets with sublimating agents

Ingredients (mg)	F16	F17	F18	F19	F20	F21	F22	F23	F24	F25	F26	F27
Camphor	5	10	15	20	-	-	-	-	-	-	-	-
Thymol	-	-	-	-	5	10	15	20	-	-	-	-
Menthol	-	-	-	-	-	-	-	-	5	10	15	20
Avicel PH102	51	46	41	36	51	46	41	36	51	46	41	36
Lactopress	25	25	25	25	25	25	25	25	25	25	25	25
Mannitol	15	15	15	15	15	15	15	15	15	15	15	15
Talc	2	2	2	2	2	2	2	2	2	2	2	2
Magnesium stearate	2	2	2	2	2	2	2	2	2	2	2	2

Technology Followed - Effervescent

Fast dissolving tablets were prepared by using citric acid and sodium-bi-carbonate in combination in (1:2 ratio) with other excipients shown in Table 3.3 was co-grounded in glass pestle glass mortar. These tablets contain (1-5% w/w) effervescent agent.^31-33

Table 4.3: Formulation of drug free tablet with effervescent technology

Ingredient (mg)	F28	F29	F30	F31	F32
Citric Acid	0.33	0.66	1.00	1.32	1.65
NaHCO₃	0.67	1.34	2.00	2.68	3.35
Avicel PH 102	55	54	53	52	51
Lactopress	25	25	25	25	25
Mannitol	15	15	15	15	15
Talc	2	2	2	2	2
Magnesium stearate	2	2	2	2	2

PRE-COMPRESSION CHARACTERIZATION

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

Bulk Density

Apparent bulk density (ρ_b) was determined by pouring the blend into a graduated cylinder. The bulk volume (V_b) and weight of powder (M) was determined.^34-37 The bulk density was calculated using the formula

Tapped Density

The measuring cylinder containing a known mass of blend was tapped 100 times using density apparatus. The constant minimum volume (V_t) occupied in the cylinder after tappings and the weight (M) of the blend was measured.^34-37 The tapped density (ρ_t) was calculated using the formula

Compressibility Index

The simplest way for measurement of flow of the powder was its compressibility, an indication of the ease with which a material can be induced to flow. ^34-37 It is expressed as compressibility index (I) which can be calculated as follows

where, ρ_t = Tapped density; ρ_b = Bulk density

Table 4.4: Compressibility index as an indication of powder flow properties

Compressibility Index (%)	Type of flow
>12	Excellent
12-16	Good
18-21	Fair to passable
23-35	Poor
33-38	Very poor
>40	Extremely poor

Hausner’s Ratio

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

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

Lower Hausner’s ratio (<1.25) indicates better flow properties than higher ones.³⁴

Angle of Repose

Angle of Repose was determined using funnel method. The blend was poured through a funnel that can be raised vertically until a specified cone height (h) was obtained. Radius of the heap (r) was measured and angle of repose (θ) was calculated using the formula^38-40

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

Table 4.5: Angle of repose as an indication of powder flow properties

Angle of repose(^o)	Type of flow
<25	Excellent
25-30	Good
30-40	Passable
>40	Very poor

Table 4.6: Characterization of drug free tablets blend

Formulation Codes	Parameters
Formulation Codes	Bulk Density (gm/cc)	Tapped Density (gm/cc)	Hausner’s Ratio	Compressibility Index (%)	Angle of Repose (^o)
F1	0.396±0.012	0.424±0.013	1.071±0.012	6.604±1.330	23.34±1.363
F2	0.403±0.015	0.429±0.012	1.065±0.024	5.621±1.233	25.19±1.221
F3	0.398±0.023	0.417±0.021	1.048±0.013	4.556±1.422	27.35±1.007
F4	0.386±0.004	0.409±0.002	1.059±0.015	5.623±1.221	24.44±1.126
F5	0.398±0.013	0.427±0.005	1.073±0.010	6.792±1.012	25.99±1.096
F6	0.371±0.025	0.395±0.006	1.065±0.003	6.076±1.231	23.56±1.132
F7	0.408±0.034	0.436±0.014	1.069±0.006	6.422±1.086	26.59±1.165
F8	0.383±0.013	0.405±0.017	1.057±0.016	5.432±1.097	26.32±1.136
F9	0.389±0.017	0.421±0.023	1.082±0.027	7.601±1.242	25.22±1.432
F10	0.396±0.006	0.434±0.023	1.095±0.010	8.756±1.134	23.59±1.243
F11	0.405±0.023	0.429±0.012	1.059±0.015	5.594±1.123	25.62±0.968
F12	0.402±0.005	0.429±0.007	1.067±0.023	6.294±1.324	23.54±0.847
F13	0.381±0.013	0.401±0.016	1.052±0.004	4.987±1.354	24.65±1.166
F14	0.378±0.008	0.396±0.004	1.047±0.007	4.545±1.087	22.67±1.124
F15	0.408±0.021	0.436±0.012	1.068±0.016	6.422±1.035	25.22±1.068
F16	0.418±0.013	0.449±0.008	1.074±0.006	6.904±1.046	26.62±1.035
F17	0.399±0.046	0.438±0.012	1.097±0.034	8.904±1.143	28.61±1.241
F18	0.401±0.035	0.443±0.010	1.105±0.023	9.481±1.135	25.32±1.146
F19	0.395±0.023	0.439±0.022	1.111±0.013	10.022±1.146	27.69±1.253
F20	0.403±0.012	0.432±0.034	1.071±0.017	6.713±1.234	27.54±0.846
F21	0.399±0.031	0.435±0.032	1.090±0.024	8.276±1.124	28.87±0.955
F22	0.407±0.014	0.441±0.023	1.084±0.032	7.709±1.146	29.21±0.866
F23	0.371±0.043	0.415±0.042	1.119±0.043	10.602±1.134	28.34±1.244
F24	0.389±0.023	0.423±0.034	1.087±0.022	8.038±1.152	27.52±1.136
F25	0.391±0.005	0.429±0.013	1.065±0.020	8.858±1.098	26.45±0.957
F26	0.401±0.024	0.439±0.022	1.095±0.019	8.656±1.153	27.61±0.697
F27	0.379±0.021	0.419±0.041	1.106±0.023	10.554±1.136	29.64±0.957
F28	0.584±0.023	0.666±0.039	1.140±0.024	12.281±1.906	23.29±0.897
F29	0.610±0.027	0.695±0.035	1.140±0.015	12.292±1.202	23.86±0.801
F30	0.625±0.030	0.721±0.028	1.153±0.026	13.307±2.018	25.58±0.856
F31	0.658±0.024	0.749±0.031	1.139±0.024	12.203±1.925	27.69±1.041
F32	0.635±0.014	0.742±0.011	1.168±0.010	14.427±0.775	29.62±0.925

±SD, n=6.

POST-COMPRESSION CHARACTERIZATION

After compression of powder blends, the prepared tablets were evaluated for organoleptic characteristics like color, odor, taste, diameter, thickness and physical characteristics like hardness, friability, disintegration time, wetting time, dispersion time. The results are shown in Table 3.16.

General Appearance

The general appearance of a tablet, its visual identification and over all ‘elegance’ is essential for consumer acceptance. This includes tablet’s size, shape, color, presence or absence of an odor, taste, surface texture, physical flaws etc.⁴¹

Tablet Thickness

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

Weight Variation

The weight variation test would be satisfactory method of determining the drug content uniformity. As per USP⁴², twenty tablets were taken and weighted individually, calculating the average weight, and comparing the individual tablet weights to the average. The average weight of one tablet was calculated.

Table 4.7: Weight variation limits for tablets as per USP

Average Weight of Tablets (mg)	Maximum % Difference Allowed
130 or less	10
130-324	7.5
More than 324	5

Hardness

Hardness of tablet is defined as the force applied across the diameter of the tablet in order to break the tablet. The resistance of the tablet to chipping, abrasion or breakage under condition of storage transformation and handling before usage depends on its hardness. Hardness of the tablet of each formulation was determined using Pfizer Hardness Tester.^41, ⁴³

Friability

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

Where, W₀ is initial weight of the tablets before the test and W is the weight of the tablets after test.^41, ⁴⁴

Wetting Time

Wetting time of the tablets was measured using a piece of tissue paper (12 cm x10.75 cm) folded twice, placed in a small petridish (ID = 6.5 cm) containing 6 ml of Sorenson’s buffer (pH 6.8). A tablet was put on the paper, and the time for the complete wetting was measured.^35, ^45-47

In Vitro Dispersion Time

In vitro dispersion time was measured by dropping a tablet in a glass cylinder containing 6 ml of Sorenson’s buffer (pH 6.8). Six tablets from each formulation were randomly selected and in vitro dispersion time was performed.^46, ^48, ⁴⁹

ANALYTICAL TECHNIQUES AND PREFORMULATION STUDIES

Drug Analysis

Melting Point: The melting point of the prochlorperazine maleate was determined by capillary fusion method. A capillary was sealed at one end filled with a small amount of prochlorperazine maleate and the capillary was kept inverted i.e. sealed end downwards into the melting point apparatus.¹³

Reported Melting Point: 229^o Observed Melting Point: 230^o

Infrared Spectral Assignment: The FTIR analysis of the sample was carried out for qualitative compound identification. The pellet of approximately 01 mm diameter of the prochlorperazine maleate was prepared grinding 3-5 mg of sample with 100-150 mg of potassium bromide in pressure compression machine. The sample pellet was mounted in FTIR (8400S, Shimadzu) compartment and scanned at wavelength 4000 – 500 cm^-1. On analysis of the FTIR spectra of the reference spectra (Fig.4.3) given in Clarke Analysis and pure prochlorperazine maleate (Fig.4.4), no major differences were observed in the characteristic absorption peak (751, 1220, 1280, 1569 cm⁻¹) pattern.

Solubility: The solubility of prochlorperazine maleate was determined in different solvent systems. Small amounts of the prochlorperazine maleate was added to 5 ml of each solvent in screw capped glass tubes and shaken. The solutions were examined physically for the absence or presence of prochlorperazine maleate particles. Qualitative solubility determined by UV- Spectrophotometer at 254 nm.

Table 4.8: Solubility profile of prochlorperazine maleate

Solvent	Solubility	Solubility (gm/ml)
Distill Water	+	0.002±0.01
0.1N Hydro Chloride	++	0.041±0.016
0.1N Sodium Hydroxide	++	0.057±0.029
Ethanol	+++	0.231±0.028
Ether	++	0.049±0.031
Chloroform	++	0.062±0.023
Buffer (pH 6.8)	++	0.055±0.011
Acetone	-	-

Freely soluble +++ Soluble ++ Slightly soluble + Practically insoluble -

Ultraviolet Absorption Maxima:

Preparation of Sorenson’s Buffer (pH 6.8)

24.5 ml of 0.2 M dibasic sodium phosphate and 0.2 M 25.5 ml of monobasic sodium phosphate was placed in 100 ml volumetric flask, and make up the volume 100 ml by water. UV spectra absorption in the rage 200 to 400 nm of a 50 g/ml solution in Sorenson’s buffer (pH 6.8) was measured.

The absorption maxima (λ_max)of prochlorperazine maleate (50 µg/ml) in the solution was found to be 254 nm and 305 nm which was concordant with the Clarke Analysis shown in Table 4.9 and Fig.4.5.

Table 4.9: Determination of wavelength maxima (λ_max)

Wavelength (nm)	Absorbance
200	0.612
224	0.337
254	0.682
274	0.035
305	0.084
361	0.003

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

200

225

250

275

300

325

350

375

400

Wavelength (nm)

Preparation of Calibration Curve:

Prochlorperazine maleate (100 mg) was dissolved in small amount of Sorenson’s buffer (pH 6.8) in a 100 ml of volumetric flask and final volume was made with the Sorenson’s buffer. 10 ml of this solution was diluted to 100 ml with Sorenson’s buffer (pH 6.8) in a 100 ml volumetric flask to obtain a stock solution of 100 µg/ml. Aliquots of 1, 2, 3, 4, 5, 6 and 7 ml were taken from stock solution in 10 ml volumetric flasks and volume was made up to 10 ml with buffer (pH 6.8). The absorbance of these solutions was measured at 254 nm. The calibration curve was plotted between concentration and absorbance.

Table 4.10: Calibration curve of prochlorperazine maleate

Concentration (µg/ml)	Absorbance (254 nm)
0	0
10	0.155
20	0.294
30	0.423
40	0.551
50	0.674
60	0.815
70	0.941

Drug-Polymer Interaction Studies

While designing fast dissolving tablets, it was imperative to give consideration to the compatibility of prochlorperazine maleate and polymer used within the systems. It was therefore necessary to confirm the interaction between polymer and drug under experimental conditions (40±5⁰ and 75±5% RH) for 4 weeks. The physical changes like discoloration, liquefaction and clumping of material were observed after regular interval of a week. The infrared absorption spectra of 4 week aged physical mixture of polymer and prochlorperazine maleate are run between 4000 - 500 cm^-1. The FTIR spectra of physical mixture of polymers and prochlorperazine maleate are shown in Fig.4.7-4.13. The absorption maxima of the prochlorperazine maleate polymer mixture were determined to know the any effect on the analysis of formulation sample. No interaction was seen between prochlorperazine maleate and polymer. The results are shown in Table 4.11.

Table 4.11: Prochlorperazine maleate polymer(s) interaction studies

Mixture	Week 1 Physical Changes	Week 2 Physical Changes	Week 3 Physical Changes	Week 4
Mixture	Week 1 Physical Changes	Week 2 Physical Changes	Week 3 Physical Changes	Physical Changes	FTIR peaks (cm⁻¹)	max (nm)
PCP	-	-	-	-	752, 1281, 1566, 1221	254, 305
PCP+Ac-di-sol	-	-	-	-	754, 1281,1571, 1219	254, 305
PCP+SSG	-	-	-	-	750, 1282,1566, 1220	254
PCP+Crospovidone	-	-	-	-	751, 1283,1569, 1222	254, 305
PCP +Menthol	-	-	-	-	746, 1279,1566, 1220	254
PCP +Camphor	-	-	-	-	751, 1278,1566, 1220	254
PCP +Thymol	-	-	-	-	751, 1279,1566, 1220	254, 304
PCP +NaHCo₃ +Citric Acid	-	-	-	-	1580, 1220	253

Physical changes: (-) Sign implies – No change

POST-COMPRESSION CHARACTERIZATION

General Appearance

Tablet Thickness

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

Weight Variation

Table 4.12: Weight variation limits for tablets as per USP

Average Weight of Tablets (mg)	Maximum % Difference Allowed
130 or less	10
130-324	7.5
More than 324	5

Hardness

Friability

Where, W₀ is initial weight of the tablets before the test and W is the weight of the tablets after test.^41, ⁴⁴

Wetting Time

In Vitro Dispersion Time

Disintegration Test

Disintegration of fast disintegrating tablets is achieved in the mouth owing to the action of saliva, however amount of saliva in the mouth is limited and no tablet disintegration test was found in USP and IP to simulate in vivo conditions.^50-53 A modified disintegrating apparatus method was used to determine disintegration time of the tablets. A cylindrical vessel was used in which 10-mesh screen was placed in such way that only 2 ml of disintegrating or dissolution medium would be placed below the sieve (Fig. 3.26). To determine disintegration time, 6 ml of Sorenson’s buffer (pH 6.8), was placed inside the vessel in such way that 4 ml of the media was below the sieve and 2 ml above the sieve. Tablet was placed on the sieve and the whole assembly was then placed on a shaker.

The time at which all the particles pass through the sieve was taken as a disintegration time of the tablet. Six tablets were chosen randomly from the composite samples and the average value was determined.⁴³

Table 4.13: Post-compression characterization

Formulation Codes	Parameters
Formulation Codes	Thickness (mm)	Weight (mg)	Hardness (kg/cm²)	Friability (%)	Wetting Time (s)	Dispersion Time (s)	Disintegration Time (s)
F1	2.436±0.012	97.1±3.512	3.2±0.128	0.421±0.069	103±2.25	105±1.07	110±1.69
F2	2.421±0.015	95.4±3.746	3.1±0.133	0.484±0.046	84±2.47	88±3.59	91±1.37
F3	2.414±0.011	98.2±4.341	3.2±0.142	0.644±0.073	61±1.48	66±3.19	72±2.48
F4	2.425±0.011	96.1±3.134	3.2±0.123	0.765±0.063	40±3.43	47±3.58	50±1.63
F5	2.437±0.009	98.6±3.561	3.1±0.134	0.873±0.057	28±2.42	39±2.10	41±3.26
F6	2.412±0.011	97.3±2.891	3.1±0.122	0.412±0.025	112±1.48	125±1.96	128±1.83
F7	2.445±0.008	96.6±3.140	3.1±0.097	0.465±0.023	87±1.69	94±2.59	96±2.41
F8	2.425±0.017	98.1±2.971	3.2±0.124	0.526±0.054	66±2.65	72±2.18	81±2.06
F9	2.431±0.014	102.1±4.128	3.1±0.132	0.766±0.013	45±1.58	51±3.51	66±3.14
F10	2.408±0.012	99.4±3.671	3.0±0.116	0.923±0.025	40±3.58	45±3.72	58±2.95
F11	2.421±0.018	98.1±2.982	3.0±0.134	0.584±0.032	98±1.07	100±2.50	99±1.09
F12	2.396±0.013	97.5±3.656	3.0±0.121	0.509±0.053	82±1.86	86±1.06	84±2.38
F13	2.426±0.014	101.5±4.413	3.1±0.143	0.456±0.014	56±2.60	58±1.18	61±1.48
F14	2.401±0.019	99.4±3.140	3.2±0.068	0.412±0.017	31±2.78	34±2.42	36±3.48
F15	2.417±0.016	101.7±2.414	3.1±0.089	0.404±0.024	22±1.12	25±2.47	27±2.30
F16	2.385±0.014	94.4±0.128	3.0±0.132	0.573±0.032	82±2.59	88±3.17	94±1.69
F17	2.409±0.017	90.1±1.124	3.0±0.141	0.606±0.037	59±1.48	61±2.75	63±2.08
F18	2.414±0.009	86.7±2.317	2.9±0.137	0.984±0.026	34±1.08	36±3.72	42±2.16
F19	2.426±0.017	80.4±3.146	3.0±0.131	1.119±0.021	18±3.44	20±1.49	32±3.27
F20	2.412±0.008	95.7±0.149	3.0±0.213	0.576±0.024	91±2.26	99±2.06	102±1.30
F21	2.396±0.012	92.2±2.426	2.9±0.146	0.613±0.054	64±2.59	68±2.59	75±1.95
F22	2.379±0.015	88.3±0.107	2.9±0.135	0.997±0.042	46±1.92	49±1.07	51±2.16
F23	2.371±0.012	84.8±1.216	2.8±0.145	1.246±0.027	28±2.48	30±1.49	35±2.59
F24	2.424±0.009	95.2±0.141	3.1±0.124	0.668±0.015	69±1.55	73±3.48	85±1.37
F25	2.417±0.016	90.3±0.019	3.0±0.186	0.789±0.019	55±2.70	59±2.38	63±1.19
F26	2.394±0.014	84.4±1.126	3.0±0.136	0.969±0.013	29±3.64	32±1.68	39±3.41
F27	2.375±0.011	80.3±0.219	3.0±0.142	1.396±0.026	15±1.69	18±3.84	30±2.48
F28	2.344±0.034	97.9±1.176	3.1±0.252	0.67±0.143	75±3.51	78±4.50	78±3.05
F29	2.363±0.035	99.6±3.765	3.0±0.276	0.78±0.129	64±2.08	65±3.05	69±3.05
F30	2.343±0.016	98.4±3.551	2.8±0.226	0.96±0.159	38±2.51	41±3.51	43±2.30
F31	2.366±0.041	98.5±3.654	2.8±0.234	1.19±0.134	29±2.08	32±2.08	35±1.52
F32	2.521±0.339	100.4±2.246	2.7±0.257	1.27±0.172	20±1.52	22±2.51	29±1.00

DEVELOPMENT OF COMBINATIONAL DRUG FREE TABLETS

The fast dissolving tablets were prepared by the combination of two disintegrants to check their influence on the pre and post compression characteristics of the tablets. These tablets were prepared as methods described earlier. Only the least concentration of the disintegrants was used in tablets to evaluate their combined effect. The blends and tablets were characterized as described earlier. The formulation of the tablet is tabulated in Table 3.17.

Table 4.14: Combined formulation of drug free tablet

Ingredients (mg)	F33	F34	F35	F36	F37	F38
Ac-di-sol	1	-	-	-	-	-
SSG	-	1	-	-	-	-
Camphor	-	-	2.5	-	-	-
Menthol	-	-	-	2.5	-	-
Thymol	-	-	-	-	5	-
Effervescent	-	-	-	-	-	1
Crospovidone	1	1	1	1	1	1
Avicel PH102	54	54	52.5	52.5	50	54
Lactopress	25	25	25	25	25	25
Mannitol	15	15	15	15	15	15
Talc	2	2	2	2	2	2
Magnesium tearate	2	2	2	2	2	2

Table 4.15: Pre-compression tablet characterization

Characterization

F33

F34

F35

F36

F37

F38

Bulk Density (g/cc)

0.587

±0.013

0.599

±0.014

0.429

±0.012

0.360

±0.005

0.426

±0.007

0.629

±0.010

Tapped Density (g/cc)

0.759

±0.039

0.857

±0.032

0.511

±0.005

0.413

±0.003

0.471

±0.009

0.682

±0.015

Hausner’s Ratio

1.392

±0.055

1.431

±0.051

1.192

±0.025

1.148

±0.019

1.106

±0.014

1.084

±0.008

Compressibility Index (%)

22.481

±3.295

30.066

±2.537

16.064

±1.782

12.910

±1.489

16.231

±0.326

7.759

±0.658

Angle of Repose (^o)

36.533

±0.501

38.557

±0.505

25.820

±0.459

25.020

±0.761

25.940

±0.516

24.533

±0.616

±SD, n=6.

Table 4.16: Post-compression characterization of drug free tablets

Characterization

F33

F34

F35

F36

F37

F38

Weight

(mg)

100.20

±0.966

99.86

±0.266

94.083

±0.878

94.940

±1.195

93.380

±0.960

100.030

±0.121

Hardness

(kg/cm²)

3.0

±0.058

2.9

±0.116

2.9

±0.141

3.0

±0.042

3.0

±0.011

3.1

±0.014

Friability (%)

1.225

±0.059

1.375

±0.029

0.525

±0.032

0.659

±0.095

0.608

±0.032

0.626

±0.041

Disintegration

Time (s)

±3.25

±2.14

±1.19

±3.84

±2.13

±1.58

±SD, n=6.

From this study, it was clears that the combined effect of disintegrants with crospovidone shows the better results on the properties of the tablets.^54, ⁵⁵ The friability of the tablets was decreased by the incorporation of the crospovidone. The disintegration time of the prepared tablets was also decreased by the crospovidone.

In the batches, F33 and F34 fair to passable flow of blends were observed. The Hausner’s ratio was found greater than 1.25 and compressibility index was found more than 16%. The poor flow of the blends were also evidenced by the angle of repose, the values were higher than 30^o. Hence it was clears, if a physical mixture of superdisintegrant was used in high speed tabletting; the problem of segregation of the disintegrants may be encountered.

The attempt was made to overcome these problems by the coprocessing of superdisintegrants (Ac-di-sol with crospovidone and sodium starch glycolate with crospovidone).

DEVELOPMENT OF FDT BY COPROCESSED SUPERDISINTEGRANTS

Coprocessing is defined as combining two or more established excipients by an appropriate process. Coprocessing of excipients by could lead to formation of excipients with superior properties compared with simple physical mixture of their components or with individual components.⁵⁵

Preparation of Coprocessed Disintegrant Blends

The coprocessed superdisintegrant was prepared as follows. Blends of Ac-di-sol/SSG and crospovidone in different ratios (1:1, 1:2, 1:3, 2:1, 2:3, 3:1, and 3:2) total weight of 10 g was added to 50 ml of isopropyl alcohol. The content of beaker was stirred on a magnetic stirrer at 50 rpm. The temperature was maintained between 65-70⁰ and stirring was continued till most of isopropyl alcohol evaporated. The wet coherent mass was sieved through sieve number 100. The wet powder was dried in a tray drier at 60⁰ for 20 min. The dried powder sifted on 120 mesh sieve and stored in airtight container until further used. For the preliminary study and evaluation only coprocessed superdisintegrant was prepared in 1:1 ratio. Rest of ratio was prepared for the factorial design batch/optimization.

Evaluation of Coprocessed Disintegrant Blends

Particle size analysis

The microscopic technique was used to test the particle size distribution of superdisintegrants and their blends. The particle size of the disintegrants was evaluating to prepare the slides of powder and observes under the microscope. To test the swelling of superdisintegrant in water and Sorenson’s buffer (pH 6.8, saliva pH), disintegrant powder were first dispersed in a small volume of liquid and the ultrasonicated for 10 min. The suspension transferred with a pipette to a small volume on the glass slide. The ratio of particle diameter in the dispersing medium to the dry powders was used as an intrinsic swelling capacity of super disintegrant in the test medium.

250

200

150

100

Dry powder

Water pH 6.8

Fig. 4.17: Particle size analysis

Mass- volume relationship and flow properties

For the mass-volume relationship bulk density (ρb), tapped density (ρt), Hausner’s ratio (R_H = ρt / ρb) and compressibility index (I_c =100 (ρt – ρb) / ρb) was determined with the bulk/tapped densitometer. The angle of repose was determined using funnel method. The blend was poured through a glass funnel that can be raised vertically until a specified cone height (h) was obtained. Radius of the conical pile (r) was measured and angle of repose (θ) was calculated using the formula tan θ = h/r.^34-40

The results are shown in Table 4.17.

Table 4.17: Evaluation of superdisintegrant

Batch

Ratio

Bulk Density

(g/cc)

Tapped Density

(g/cc)

Hausner’s Ratio

Compressibility Index

(%)

Angle of Repose (%)

Ac-di-sol

0.742

±0.019

0.911

±0.034

1.235

±0.011

21.059

±0.119

38.18

±0.106

SSG

0.759

±0.005

0.945

±0.004

1.250

±0.004

20.029

±0.234

36.18

±0.174

Crospovidone

1.244

±0.020

1.858

±0.015

1.494

±0.034

33.039

±1.519

44.02

±1.010

Physical Mixture (Ac-di-sol

+Crospovidone)

1:1

0.785

±0.004

1.131

±0.009

1.312

±0.016

25.946

±1.153

39.96

±1.623

Physical Mixture (SSG+

Crospovidone)

1:1

0.891

±0.008

1.157

±0.040

1.299

±0.039

22.946

±2.268

37.83

±1.714

Coprocessed (Ac-di-sol

+Crospovidone)

1:1

0.512

±0.080

0.601

±0.017

1.173

±0.023

14.801

±0.218

24.16

±0.529

Coprocessed (SSG+

Crospovidone)

1:1

0.624

±0.002

0.700

±0.004

1.122

±0.004

10.856

±0.332

22.42

±0.626

±SD, n=6.

Scanning electron micrographs

Finally to investigate the morphology of SSG, crospovidone and prepared coprocessed superdisintegrant, scanning electron micrographs were taken using (JOEL, JSM-35, CF) scanning electron microscope; where the samples were previously sputter coated with gold.⁵⁶

Fig. 4.18: Scanning electron micrographs

A. Crospovidone; B. Ac-di-sol; C. Sodium starch glycolate; D. Coprocessed Ac-di-Sol + Crospovidone; E. Coprocessed Sodium starch glycolate + Crospovidone

Preparation of FDT with Coprocessed Superdisintegrants

The fast dissolving tablets were prepared with coprocessed superdisintegrants (Ac-di- sol with crospovidone and sodium starch glycolate with crospovidone) and evaluated for pre and post-compression properties. The evaluated parameters were compared with the tablets prepared by physical mixture of superdisintegrants. The formulation and evaluations are tabulated in Table 4.18.

Table 4.18: Development of tablets with coprocessed superdisintegrants

FORMULATION
Ingredients (mg)	F39	F40
Ac-di-sol	1	-
Sodium starch glycolate	-	1
Crospovidone	1	1
Avicel PH102	54	54
Lactopress	25	25
Mannitol	15	15
Talc	2	2
Magnesium stearate	2	2
PRE-COMPRESSION CHARACTERIZATION
Bulk Density (gm/cc)	0.407 ±0.012	0.438±0.021
Tapped Density (gm/cc)	0.453 ±0.011	0.510 ±0.009
Hausner’s Ratio	1.112 ±0.007	0.587 ±0.013
Compressibility Index (%)	10.097 ±0.552	1.167 ±0.041
Angle of Repose (^o)	23.217 ±0.901	22.470 ±1.265

POST-COMPRESSION CHARACTERIZATION
Weight (mg)	100.01±0.388	99.76±0.188
Hardness (kg/cm²)	3.5±0.100	3.4±0.091
Friability (%)	0.629±0.018	0.623±0.015
Disintegration Time (s)	72±1.18	76±1.26

±SD, n=6.

120

100

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

T33 T39 T35 T40 T33 T39 T35 T40

Fig. 4.19: Comparison of tablets prepared by physical mixture and coprocessed superdisintegrants

PREPARATION OF DRUG FREE TABLETS

Drug free fast dissolving tablets were prepared by direct compression method because of their several advantages.^23-25

· Easiest way to manufacture tablets.

· High doses can be accommodated.

· Use of conventional equipment.

· Use of commonly available excipients.

· Limited number of processing steps.

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