Application of a Newly Developed Multifunctional Excipient in Tablet Formulation

 

Anthony O. Onyekweli¹, Olobayo O. Kunle² and Ebere I. Okoye¹*

¹Department of Pharmaceutics and Pharmaceutical Technology, Faculty of Pharmacy,

University of Benin, Benin City, Edo State, Nigeria

²Department of Pharmaceutical Technology and Raw Materials Development,

National Institute for Pharmaceutical Research and Development (NIPRD), Idu, Abuja, Nigeria

*Corresponding Author E-mail: ebypiaen@yahoo.com

 

The aim of this study was to investigate the applicability of a newly developed multifunctional excipient series, Lacagpregs, in the formulation of tablets by direct compression and wet granulation methods. Active ingredients (metronidazole, chloroquine phosphate and paracetamol) powders that exhibit poor compaction profiles were used to challenge the new excipient series. The qualities of tablets formulated using the novel excipients via direct compression (metronidazole and chloroquine phosphate tablets) and wet granulation (paracetamol tablets) methods were evaluated using standard protocols. These were then compared to the qualities of similar tablets (metronidazole, chloroquine phosphate and paracetamol tablets) formulated with the physical mixtures of the new excipients’ components, Avicel® PH 101 (metronidazole and chloroquine phosphate tablets), or Povidone K15/pregelatinized starch mixture (paracetamol tablets). The qualities of tablets formulated with the novel excipient compared well with those of tablets formulated with standard excipients (PVP and Avicel® PH 101) and  some commercial products in Nigerian market; and in some cases were significantly (p < 0.05) better than both. Among the new excipient series, concentration of the primary plastic material and duration of processing greatly influenced their functionality as tableting excipients, whereas intensity of agitation produced unremarkable influence.  It is therefore evident that the new excipient series which were designed to function as binder-filler-disintegrant can be employed in tablet formulation via both direct compression and wet granulation processes. 

 

 

INTRODUCTION:

Excipient is a term coined from the Latin word excipiens. It is the present participle of the verb excipere which means to receive, to gather, and to take out. This refers to one of the properties of an excipient, which is to ensure that a medicinal product has the weight, consistency, and volume necessary for the correct administration of the active principle to the patient.¹ Excipients are considered as “inert” components of a drug delivery system (DDS), hence they are referred to as adjuncts, adjuvants, or additives. With more than 70% of formulations containing excipients at a concentration higher than the active drug, it further suggests that excipients contribute significantly towards the processing and functioning of the formulation.

 

Over the years, an increasing appreciation of the excipients’ role in solid dosage forms has triggered their metamorphosis from being “inert ingredients” to functional components of the formulation.²  This informs the current definition of an excipient as: any substance other than the active drug or product which has been appropriately evaluated for safety and is included in DDS to either, aid processing of the DDS during manufacture, protect, support or enhance stability, bioavailability or patient acceptability, aid in product identification, or provide any other attribute of the overall safety and effectiveness of the entire drug product during storage and use.³  A multifunctional excipient is one that performs more than one function in a dosage form. For example microcrystalline cellulose, a classical multifunctional excipient can function as binder, filler, disintegrant and lubricant, thereby eliminating the need for individual excipients that perform these separate functions; and invariably leading to reduction in total costs in time and money for the production process. Pharmaceutical tablets are the principal dosage form for drug delivery, representing two-thirds of the global market⁴.  The main reasons for their continued popularity are the ease of manufacture, convenience of dosing, and large storage stability in comparison with liquid and semi-solid formulations. Direct compression of the active ingredient with adequate excipients is one of the most advantageous processes for tablet manufacture.⁵ Compactibility is necessary for satisfactory tableting (i.e., the powder must remain in the compact form once the compression force is removed) ⁶, and for poorly compressible active ingredient powders, excellent excipients are needed for their conversion from powders to stable tablet dosage forms. The aim of the study therefore is to investigate the applicability of a new multifunctional excipient in tablet formulation via wet granulation and direct compression.

 

MATERIALS AND METHODS:

Materials

These include Lacagpregs, a series of novel excipients formulated (using the experimental design shown below) with lactose, cashew gum and partially pregelatinized starch at fixed concentrations via a new particle engineering technique ⁷, Avicel^® PH 101 (Fluka, Switzerland), polyvinyl pyrrolidone K 15 (Fluka, USA ), partially pregelatinized starch (PGS), generated from Corn starch B.P. (Sigma-Aldrich, Germany) by BPC (1979) method, magnesium stearate (BDH Chem., UK), paracetamol powder (Mallirickrodt Inc., USA), metronidazole powder (Zhejiang chemical, China), chloroquine phosphate powder (TNN development Ltd, China), paracetamol 500 mg tablets (Emzor Pharmaceuticals, Nigeria), metronidazole 400 mg tablets (Loxagyl M&B Pharmaceuticals, Nigeria) and chloroquine 250 mg tablets (Evans Pharmaceuticals, Nigeria). Other reagents were of analytical standard.

 

Experimental design:

L₁M₁T₁₀  L₁M₁T₃₀  L₁M₁T₆₀

L₁M₂T₁₀  L₁M₂T₃₀  L₁M₂T₆₀

L₁M₃T₁₀  L₁M₃T₃₀  L₁M₃T₆₀

L₁M₄T₁₀  L₁M₄T₃₀  L₁M₄T₆₀

L₁M₅T₁₀  L₁M₅T₃₀  L₁M₅T₆₀

L₂M₁T₁₀  L₂M₁T₃₀  L₂M₁T₆₀

L₂M₂T₁₀  L₂M₂T₃₀  L₂M₂T₆₀

L₂M₃T₁₀  L₂M₃T₃₀  L₂M₃T₆₀

L₂M₄T₁₀  L₂M₄T₃₀  L₂M₄T₆₀

L₂M₅T₁₀  L₂M₅T₃₀  L₂M₅T₆₀

L₃M₁T₁₀  L₃M₁T₃₀  L₃M₁T₆₀

L₃M₂T₁₀  L₃M₂T₃₀  L₃M₂T₆₀

L₃M₃T₁₀  L₃M₃T₃₀  L₃M₃T₆₀

L₃M₄T₁₀  L₃M₄T₃₀  L₃M₄T₆₀

L₃M₅T₁₀  L₃M₅T₃₀  L₃M₅T₆₀

PM – M₁                PM – M₂                PM – M₃               

PM – M₄                PM – M₅

L – Planetary mixer stirrer’s speed level: 1, 2, 3.

M – Cashew gum concentration: 1, 2, 3, 4, 5 %w/w.

T – Duration of stirring: 10 min, 30 min, 60 min.

PM – Physical mixture of the primary excipients at 1, 2, 3, 4, 5 %w/w cashew gums concentration.

 

 

Methods

Wet granulation method

Based on results from preliminary studies, 25 g of paracetamol powder was intimately mixed with 10 g of individual engineered (novel) excipient or its physical mixture using a planetary mixer (Kenwood, model OWHM400020) for 10 min. Thereafter the powder mix was carefully transferred into a big porcelain mortar and wet massing was done by spraying 6 ml of distilled water at room temperature (32^oC) and kneading with pestle until a homogeneous mass was formed. The wet mass was then screened through a 1000 mm stainless steel sieve and the resulting granules dried in the hot air oven at 60^oC for 1 h. The dry granules were finally screened through a 600 mm stainless steel sieve, and dried again at 60^oC for 1 h before they were stored in air tight containers over silica gel prior to tableting.^8,9,10 Granules used as control for the wet granulation process were formulated with percentage equivalents of components (i.e. 71.4 %w/w paracetamol, 13.6 %w/w lactose, 5 %w/w polyvinylpyrrolidone (PVP), and 10 %w/w PGS) in the test granules. The resulting granules were mixed with 0.5% w/w of magnesium stearate in the planetary mixer for 5 min prior to compaction. Seven hundred milligrams (700 mg) of the paracetamol granules were accurately weighed and carefully transferred into one die of the tableting machine (JC – RT - 24H, Jenn Chiang Machinery Co., LTD, Feng – Yuan, Taiwan) and compressed with a force of 15 KN. The resulting tablets were stored in air tight containers over silica gel for 7 days before relevant quality control tests were conducted on them.

 

Direct compression method

Based on results from preliminary studies, 15 g of metronidazole, 15 g of the novel excipient or its physical mixture were mixed using the planetary mixer for 10 min after which 0.15 g of magnesium stearate was added and mixing continued for another 5 min. The tablets were made individually by compressing 500 mg of the powder mix at 25 KN force in the tableting machine. The resulting tablets were stored in air-tight containers over silica gel for 7 days before relevant quality control tests were conducted on them. The control for these metronidazole tablets was formulated with 15 g of metronidazole, 15 g of microcrystalline cellulose (Avicel PH 101) and 0.15 g of magnesium stearate and compaction was at 25 KN.

 

Direct compression method was also employed in the formulation of chloroquine tablet. Based on the results from preliminary study, fifteen grams (15 g) of chloroquine phosphate, 33 g of the novel excipient or its physical mixture, were mixed in the planetary mixer for 10 min after which 0.24 g of magnesium stearate was added and mixing continued for another 5 min. Six hundred and forty milligrams (640 mg) of the powder mix were individually weighed and carefully transferred in the selected die of the tableting machine and compressed at 25 KN.

 

 

 

Fig.1: Dissolution profile of commercial metronidazole tablets and those formulated with the novel excipients, or Avicel PH 101.

 

 

 

Fig.2: Dissolution profile of commercial chloroquine phosphate tablets and those formulated with the novel excipients, or Avicel PH 101.

 

 

Fig.3: Dissolution profile of commercial paracetamol tablets and those formulated with the novel excipients, physical mixture or PVP.

 

Fig. 4: Paracetamol spectrum in 0.1N HCl

 

Fig. 5: Metronidazole spectrum in 0.1N HCl

 

Fig. 6: Chloroquine phosphate spectrum in distilled water

 

 

All the tablets were stored in air-tight containers over silica gel for 7 days before relevant quality control tests were conducted on them. The control for these chloroquine tablets was formulated with 15 g of chloroquine, 33 g of microcrystalline cellulose (Avicel PH 101) and 0.24 g of magnesium stearate and compressed at 25 KN.

 

Quality control tests on the formulated tablets

The following quality control tests were carried out on the formulated tablets, their controls and commercial equivalents available in Nigeria. The commercial equivalents are paracetamol 500 mg (Emzor), metronidazole 400 mg (Loxagyl M&B) and chloroquine phosphate 250 mg (Evans).

 

Tablet hardness

The hardness values of ten tablets selected at random from each batch were determined at room temperature (32^oC) by diametral compression using Eweka hardness tester (Karl Kolb, Erweka Germany).. Results were taken from tablets that split cleanly into two halves without any sign of lamination. The hardness values were then converted to crushing strength by multiplying them by 10 m/s² which is acceleration due to gravity.

 

 Friability of tablets

Ten tablets were de-dusted, weighed and placed in the friabilator (Copley/Erweka GmbH Type: TAR 20 Heusenstamm Germany). The apparatus was operated at 25 revolutions per minute (25 rpm) for 4 min. Thereafter the tablets were de-dusted and reweighed. The friability of the tablets was evaluated with equation 1:

 

Where W_i=initial weight of the tablets before test;  W_f= final weight of the tablets after test

 

Tablet disintegration test

The disintegration times of the tablets were determined in 800 ml distilled water at 37 ± 0.5 ^oC ¹¹ using disintegration test unit (Manesty Mk 4 Machine, UK). Six tablets were used from each batch of tablets and one tablet was introduced into each of the six tubes. The assembly was suspended in the beaker containing the distilled water at 37 ± 0.5 ^oC and the apparatus operated until all the tablets disintegrated. The time taken for each tablet to disintegrate was noted and the mean value reported.

 

Determination of the wavelength of maximum absorption (ʎ_max) and generation of Beer’s plot for each drug

The ʎ_max of each drug was determined with 10 µg/ml solution (paracetamol or metronidazole in 0.1 N HCl, chloroquine phosphate in distilled water). Each solution was scanned between 200 nm and 800 nm using UV-Visible spectrophotometer (UV– 160A Shimadzu Corporation Japan). The peak absorbance values chosen for the drugs were 296 nm, 276 nm, and 343 nm for paracetamol, metronidazole and chloroquine phosphate respectively (Figs. 4, 5, 6). Subsequently, solutions of paracetamol or metronidazole of concentrations: 2, 4, 6, 8, 10, 12 and 14 µg/ml in 0.1 N HCl and chloroquine phosphate of concentrations:  0.4, 0.8, 1.2, 1.6, 2.0, 2.4 and 2.8 µg/ml in distilled water, were prepared and their absorbance values determined at the ʎ_max of each drug using the medium as blank. The results were used to generate the Beer’s plots (Figs. 7, 8, 9) for the drugs.

 

Fig 7. Beer’s plot for chloroquine phosphate

 

Fig 8. Calibration curve for paracetamol

 

Fig 9. Calibration curve for metronidazole

 

Tablets dissolution tests

Tablets dissolution tests were  carried out according to USP XXIII basket method with  an eight chambered dissolution test machine (Erweka Germany Type: DT 80) operated at 50 rpm for 60 min in 900 ml of 0.1 N HCl for paracetamol and metronidazole, but distilled water for chloroquine phosphate tablets, and maintained at 37 ± 0.5 ⁰C . One milliliter (1 ml) of dissolution fluid was withdrawn and replaced with 1 ml of fresh medium at the following intervals: 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55 and 60 min. Each withdrawn sample was made up to 20 ml with fresh medium, filtered and its absorbance determined with the UV – Visible spectrophotometer at its ʎ_max, and its medium as blank. Duplicate determinations were conducted and the mean values used to evaluate the percentage drug released using the Beer’s plot equation for each drug and applying the appropriate dilution factor.

 

RESULTS AND DISCUSSION:

Hardness, friability, disintegration time and dissolution profile of commercial metronidazole tablets and those formulated with the novel excipients, or avicel PH 101.

Metronidazole tablets containing 250 mg of active ingredient were formulated by direct compression using the novel excipients at the ratio of 1:1. The use of the excipients below this concentration resulted in tablets with low hardness values and friability values as high as 11.0%. The hardness of metronidazole tablets formulated with physical mixtures ranged from 33.3 N to 91.7 N (MTPM – M₁ to MTPM – M₅) i.e. metronidazole tablets formulated with physical mixture at cashew gum concentration of 1.0 – 5.0%. The friability values of these tablets were 100% and this informs the decision to discontinue further studies on them. Tablets formulated with the novel excipients displayed acceptable hardness values ¹² : 56.7 N (MTL₁M₁T₁₀) to 140.0 N (MTL₁M₅T₆₀) (Table 1). These values are higher than the recommended minimum for a conventional tablet¹³.  Although the hardness values of the tablets are acceptable, the friability values of many of them were higher than 1.0% ¹³ and ranged from 0.80% (MTL₃M₅T₃₀) to 9.05% (MTL₃M₁T₁₀). Further analyses of results were therefore limited to tablets with acceptable friability values. There were no significant differences between the hardness values of MTL₂M₄T₃₀, MTL₂M₅T₃₀, MTL₂M₃T₆₀, MTL₂M₄T₆₀, MTL₂M₅T₆₀, MTL₃M₄T₃₀, MTL₃M₅T₃₀, MTL₃M₄T₆₀ and MTL₃M₅T₆₀  although numerically they appear different. This is also applicable to their disintegration times (Table 1) in which no significant difference was revealed by the analysis of variance (single factor). The mean hardness, disintegration time and friability values for metronidazole tablets formulated with Avicel PH 101, MTAVI, were 138.3 N, 11.48 min, and 0.28% respectively; while those of the commercial product, MTINN (Loxagyl 400 mg M&B Nigeria) were 141.7 N, 22.92 min, and 0.20% respectively. Application of ANOVA on the hardness values of metronidazole tablets formulated with the novel excipients and those of Avicel PH 101 and the commercial product revealed that there was no significant difference between them. However, on the analysis of disintegration times, a significant difference (p < 0.05) was revealed. The significant difference (p < 0.05) revealed for disintegration time when subjected to LSD post–hoc analysis was shown to have resulted from the disintegration time of the commercial product, which disintegrated at more than twice the duration taken by the other products. It is therefore noteworthy that the novel excipients compared favourably with the versatile binder–filler–disintegrant, Avicel¹⁴, in imparting acceptable tablet properties on metronidazole, an otherwise difficult powder to compact.^15,16 Their tablets also compared favourably with the commercial product and possessed better disintegration times.

Table 1: Properties of commercial metronidazole tablets and those formulated with the novel excipients, their physical mixtures, or Avicel PH 101 at 25KN compression pressure.

Formulation	Hardness(N)	Friability (%)	Disintegration time (min)	Formulation	Hardness(N)	Friability (%)	Disintegration time (min)
MTL1M1T10	56.70±1.607	7.41	0.25±0.050	MTL2M1T60	50.00±1.000	7.67	1.18±0.355
MTL1M2T10	66.70±1.443	6.78	0.33±0.054	MTL2M2T60	95.00±1.323	2.78	1.42±0.892
MTL1M3T10	68.30±1.607	4.17	0.57±0.250	MTL2M3T60	123.30±2.021	0.96	7.59±1.847
MTL1M4T10	81.70±1.258	3.05	0.69±0.155	MTL2M4T60	125.00±1.323	0.96	9.67±1.632
MTL1M5T10	103.30±1.756	2.02	0.74±0.146	MTL2M5T60	126.70±1.893	0.91	9.76±1.433
MTL1M1T30	75.00±2.646	6.62	0.73±0.361	MTL3M1T10	46.70±0.764	9.05	0.35±0.067
MTL1M2T30	86.70±1.258	6.05	2.32±0.808	MTL3M2T10	51.70±0.764	7.39	0.46±0.155
MTL1M3T30	113.30±2.309	3.17	6.99±2.623	MTL3M3T10	66.70±0.577	6.04	4.73±0.635
MTL1M4T30	133.30±1.528	1.45	8.44±0.151	MTL3M4T10	105.00±2.500	2.40	8.24±2.275
MTL1M5T30	133.30±2.082	1.22	9.57±0.947	MTL3M5T10	120.00±2.000	1.56	9.95±1.222
MTL1M1T60	58.30±1.756	5.17	0.67±0.233	MTL3M1T30	45.00±0.500	7.09	1.08±0.391
MTL1M2T60	76.70±2.466	4.90	3.50±0.120	MTL3M2T30	58.00±1.258	5.23	1.27±0.504
MTL1M3T60	123.30±2.255	2.32	8.04±1.428	MTL3M3T30	76.70±1.258	2.43	4.92±0.729
MTL1M4T60	136.70±1.258	1.51	12.39±6.124	MTL3M4T30	116.70±1.041	0.93	11.44±1.098
MTL1M5T60	140.00±0.500	1.06	12.54±3.611	MTL3M5T30	131.70±2.363	0.80	11.71±0.793
MTL2M1T10	58.30±1.443	8.34	1.24±0.532	MTL3M1T60	48.30±1.041	6.59	0.77±0.301
MTL2M2T10	60.00±2.000	7.57	1.53±0.602	MTL3M2T60	60.00±1.803	4.37	1.01±0.444
MTL2M3T10	80.00±2.000	4.77	3.08±1.229	MTL3M3T60	75.00±0.866	2.26	4.47±1.491
MTL2M4T10	88.30±1.258	2.22	5.80±1.648	MTL3M4T60	125.00±2.291	1.04	10.38±1.625
MTL2M5T10	93.30±1.155	1.91	7.33±0.661	MTL3M5T60	128.30±1.258	0.92	11.88±1.637
MTL2M1T30	66.70±3.055	5.06	4.34±0.577	MTPM – M1	33.30±1.443	100.00	0.11±0.010
MTL2M2T30	93.30±4.163	2.41	5.86±1.623	MTPM – M2	43.30±1.155	100.00	0.16±0.042
MTL2M3T30	111.70±2.843	1.09	6.32±2.048	MTPM – M3	51.70±1.893	100.00	0.17±0.042
MTL2M4T30	121.60±1.756	0.84	9.42±2.099	MTPM – M4	65.00±1.500	100.00	0.18±0.060
MTL2M5T30	125.00±1.500	0.89	11.29±3.163	MTPM – M5	91.70±1.041	100.00	0.25±0.050
MTAVI	138.30±1.756	0.28	11.48±7.419	MTINN	141.70±0.764	0.20	22.92±0.643

MTL₁M₁T₁₀ – metronidazole tablet formulated with L₁M₁T₁₀. MTPM – M₁ - metronidazole tablet formulated with PM – M₁.  MTINN – commercial metronidazole tablet; MTAVI – metronidazole formulated with Avicel PH 101.

 

 

 

The dissolution profile of metronidazole tablets with acceptable mechanical properties are shown in Fig. 1. The amounts of metronidazole released from tablets formulated with the novel excipients are in most cases good and compared favourably with the commercial products and those formulated with Avicel PH 101. Metronidazole tablets formulated with L₂M₄T₃₀ (MTL₂M₄T₃₀) displayed the fastest release rate, while those formulated with L₃M₅T₆₀ (MTL₃M₅T₆₀) displayed the slowest release rate. This observation may be explained by the relationship between the disintegration time and dissolution rate of conventional tablets formulated by direct compression. These formulations upon disintegration release their APIs immediately contrary to what obtains in wet or dry granulation formulations in which further granule disintegration needs to occur before the active drug is released completely. Except for MTL₃M₅T₃₀ and MTL₃M₅T₆₀, other tablets released up to 70% of their APIs within 30 min or less, which is in line with standard recommendation ¹⁷. The commercial product, MTINN, and tablets formulated with Avicel PH 101, MTAVI also met the standard recommendation and even released larger total amounts of metronidazole at the end of 60 min. The highest drug released by the commercial product may not be explained directly, although it may not be unconnected with the addition of some kind of solubility enhancer (for example fructose, povidone, or surfactant) in the formulation ^{18, 19}.    

 

Hardness, friability, disintegration time and dissolution profile of commercial chloroquine phosphate tablets and those formulated with the novel excipients, or Avicel PH 101.

Good quality chloroquine phosphate tablets were formulated with novel excipients at a ratio of 1:2.2 (i.e. 31.25%: 68.75%) chloroquine phosphate powder: novel excipient respectively. This result is attributable to the poor compaction properties of chloroquine phosphate powder and is consistent with previous report ²⁰. Furthermore, previous workers ²¹, who used pregelatinized starches as binders via direct compression, obtained chloroquine phosphate tablets of good hardness when the binders’ concentration was increased to 80%. The physical mixtures of primary excipients were unable to form tablets with chloroquine phosphate even at a ratio of 1:4 of chloroquine powder to physical mixture. The hardness values for the tablets formulated with the novel excipients ranged from 95.0 N (CQL₃M₁T₁₀) to 155.0 N (CQL₂M₅T₆₀) (Table 2). These values are higher than the accepted minimum of      40 N ¹². The commercial product, CQINN (chloroquine phosphate 250 mg Evans Nigeria) and tablets formulated with Avicel^® PH 101 at the ratio of 1:2.2 displayed hardness values of 38.3 N and 145.0 N respectively. There was no significant difference between the hardness values of all the tablets formulated with the novel excipients, and between them and those formulated with Avicel^® PH 101. This implies that the novel excipients at the same concentration imparted similar hardness values to chloroquine phosphate tablets as did Avicel^® PH 101. There was however, significant difference (p < 0.05) between the hardness of tablets formulated with the novel excipients and those of the commercial product. Post–hoc analysis revealed that the difference (p < 0.05) was caused by the low hardness of the commercial product in comparison to those of novel excipient products. It is worthy to note that although the hardness of the commercial product was less than the accepted standard, it passed the friability test (its friability value was 0.90%). The friability values for tablets formulated with the novel excipients ranged from 0.53% (CQL₂M₅T₆₀) to 1.75% (CQL₃M₁T₁₀), while the value for tablets formulated with Avicel^® PH 101 was 0.05%. Among tablets formulated with the novel excipients, sixteen batches (35.56%) passed the friability test ¹³. Avicel^® PH 101 imparted greater ability to resist abrasion to chloroquine tablets in comparison to the novel excipients. This is as a result of the very high plastic nature of Avicel^® PH 101. It therefore caused more plastic deformation ^{22, 23} on the chloroquine phosphate powder, a poorly compressible powder. The mean disintegration time values for tablets formulated with the novel excipients ranged from 8.35 min (CQL₂M₁T₁₀) to 13.33 min (CQL₁M₅T₃₀), while those of tablets formulated with Avicel^® PH 101 and the commercial product were 59.02 min and 4.29 min respectively. Except tablets formulated with Avicel^® PH 101, all the formulations met the standard required for the disintegration of conventional tablets (i.e. ≤ 15 min) ²⁴. This finding is consistent with previous reports ^{25, 26, 27} that high concentration of Avicel^® in tablets formulated via direct compression resulted in increase in disintegration time. There are significant differences (p < 0.05) between the disintegration times of the novel products and those of the commercial product and Avicel^® PH 101; and even among those of tablets formulated with the novel excipients. LSD post – hoc test on those that passed all the quality control tests revealed that the difference (p < 0.05) emanated from the disintegration times of CQL₁M₄T₆₀ and CQL₃M₄T₆₀.

 

The dissolution profile of some of the formulated and commercial chloroquine phosphate tablets are shown in Fig. 2. The tablets formulated with the novel excipients and those of the commercial product had a t₇₀ (time to release 70% of drug) of less than 30 min. Those formulated with Avicel^® PH 101 failed to meet the requirement and this is traceable to their long disintegration time since disintegration time has direct influence on dissolution characteristics of conventional tablets especially those formulated by direct compression. Further explanation of this observation is that due to high compaction pressure used (25 KN) and Avicel being a highly plastic excipient, the packing fraction of tablets formulated with it was so high and the porosity very low ^{23, 27}, thus resulting in very slow penetration of dissolution fluid into the tablet to cause disintegration and subsequent drug dissolution and release.

 

 

 

 

 

Table 2: Properties of commercial chloroquine phosphate tablets and those formulated with either the novel excipients, or Avicel PH 101 at 25KN compression pressure.

Chloroquine phosphate tablets formulated with L₁M₁T₁₀ (CQL₁M₁T₁₀), Avicel PH 101 (CQAVI). CQINN – commercial chloroquine phosphate tablet. * The physical mixtures (PMs) did not form tablets with chloroquine.

 

 

 

Table 3: Properties of commercial paracetamol tablets and those formulated with the novel excipients, their physical mixtures, or PVP at 15KN compression pressure

Formulation	Hardness(N)	Friability (%)	Disintegration time (min)	Formulation	Hardness(N)	Friability (%)	Disintegration time (min)
PCL1M1T10	110.00±1.323	1.42	10.69±0.730	PCL2M1T60	113.30±1.041	1.51	9.93±0.939
PCL1M2T10	113.00±0.764	1.42	11.37±0.811	PCL2M2T60	120.00±0.866	1.33	11.39±1.260
PCL1M3T10	121.70±1.041	1.02	11.60±1.282	PCL2M3T60	123.30±1.041	0.98	11.48±1.417
PCL1M4T10	128.30±1.528	0.95	11.54±0.627	PCL2M4T60	125.00±1.500	0.91	11.37±0.656
PCL1M5T10	131.70±0.764	0.90	12.83±0.338	PCL2M5T60	138.30±1.258	0.88	13.23±0.382
PCL1M1T30	118.30±0.764	1.56	11.37±0.677	PCL3M1T10	111.70±1.258	1.69	10.64±0.391
PCL1M2T30	120.00±2.500	1.34	11.51±0.615	PCL3M2T10	113.30±0.764	1.76	10.69±0.423
PCL1M3T30	125.00±0.500	0.97	11.87±1.034	PCL3M3T10	120.00±0.500	1.33	11.12±0.525
PCL1M4T30	128.30±1.258	0.86	12.29±0.876	PCL3M4T10	126.70±0.764	1.11	12.07±0.885
PCL1M5T30	145.00±1.0	0.82	13.48±0.614	PCL3M5T10	135.00±0.866	0.95	13.81±0.967
PCL1M1T60	113.30±0.764	1.48	10.78±0.769	PCL3M1T30	111.70±0.764	1.62	10.87±0.459
PCL1M2T60	116.70±1.041	1.40	11.94±1.109	PCL3M2T30	116.70±1.041	1.46	11.11±0.543
PCL1M3T60	121.70±0.764	0.88	12.31±0.935	PCL3M3T30	126.70±1.041	1.03	11.44±0.594
PCL1M4T60	128.30±1.041	0.92	12.47±1.056	PCL3M4T30	131.70±0.764	0.91	12.21±0.367
PCL1M5T60	143.30±0.764	0.89	13.48±0.614	PCL3M5T30	143.30±0.764	0.83	12.71±0.811
PCL2M1T10	118.30±0.764	1.53	11.22±0.738	PCL3M1T60	108.30±1.041	1.48	11.38±0.475
PCL2M2T10	126.70±1.041	1.28	11.38±1.348	PCL3M2T60	123.30±0.764	0.98	11.61±1.093
PCL2M3T10	128.30±0.289	1.12	11.13±0.640	PCL3M3T60	131.70±0.764	0.94	12.28±0.527
PCL2M4T10	131.70±1.607	0.94	11.57±0.367	PCL3M4T60	141.70±0.764	0.86	12.63±0.722
PCL2M5T10	135.00±0.500	0.94	11.65±0.650	PCL3M5T60	145.00±0.500	0.88	13.02±0.693
PCL2M1T30	111.70±1.258	1.58	10.33±1.415	PCPM – M1	108.30±1.041	4.48	10.81±0.896
PCL2M2T30	113.30±1.041	1.16	10.94±0.939	PCPM – M2	111.70±1.258	4.46	10.96±0.851
PCL2M3T30	126.70±1.258	0.98	11.31±0.360	PCPM – M3	118.30±0.289	3.88	10.94±0.801
PCL2M4T30	133.30±0.764	0.91	12.00±0.744	PCPM – M4	138.30±1.258	1.62	13.24±0.394
PCL2M5T30	136.70±1.041	0.84	12.43±1.667	PCPM – M5	143.30±1.258	0.93	13.05±0.715
PCPVP	103.30±1.528	0.88	12.88±0.530	PCINN	43.30±1.155	0.45	4.06±0.735

PCL₁M₁T₁₀ – paracetamol tablet formulated with L₁M₁T₁₀; PCPM-M₁ - paracetamol tablet formulated with PM – M₁;

PCINN – commercial paracetamol tablet; PCPVP – paracetamol formulated with PVP

 

Hardness, friability, disintegration time and dissolution profile of commercial paracetamol tablets and those formulated with the novel excipients, physical mixtures of the primary excipients, or PVP.

The physical mixtures as well as the novel excipients formed tablets at all the concentration ratios tested because of the ‘levelling effect’ of wet granulation. The hardness of tablets formulated with the physical mixtures ranged from 108.3 N (PCPM – M₁) to 143.3 N (PCPM – M₅). Those of tablets formulated with the novel excipients ranged from 108.3 N (PCL₃M₁T₆₀) to 145.0 N (PCL₁M₅T₃₀, PCL₃M₅T₆₀), while those of polyvinyl pyrrolidone (PVP) and commercial product (paracetamol 500 mg Emzor Nigeria) were 103.3 N and 43.3 N respectively (Table 3). It is interesting to note that the wet granulation process had a levelling effect on the mechanical strength of all the non commercial paracetamol tablets. This is attributable to the homogenization effect the granulating fluid and the granulation process imparted on the compaction properties of the constituent powders. The granules of lactose powder are known to undergo extensive fragmentation upon compaction thereby exposing fresh and smaller surfaces that enhance bond formation ^{28, 29}. When binders (e.g. PVP, cashew gum or even pregelatinized starch) are added to the mixture of paracetamol (an elastic powder) and lactose and wet granulated, the resulting granules usually possess enhanced plasticity ³⁰, and this accounts for the levelling effect observed in this study. Cashew gum however, was superior to PVP in improving the mechanical strength of the tablets because even at its lowest concentration, 1% w/w, tablets containing it were harder than those containing PVP at the fixed concentration of 5% w/w (Table 3). All the tablets tested passed the standard requirement on hardness for conventional tablet (i.e. hardness ≥ 40.0 N) ¹². The friability of the tablets formulated with the physical mixtures ranged from 4.48% (PCPM – M₁) to 0.93% (PCPM – M₅), those of the novel excipients ranged from 1.76% (PCL₃M₂T₁₀) to 0.82% (PCL₁M₅T₃₀), while those of the commercial product and PVP were 0.45% and 0.88% respectively. Statistical analyses on the hardness of tablets that passed the friability test revealed that the hardness values of tablets formulated with the physical mixtures were not significantly different from those of tablets formulated with the novel excipients, thus confirming the levelling effect of wet granulation method discussed above. The difference between the hardness values of tablets formulated with PVP and those of tablets formulated with the novel excipients was statistically significant (p < 0.05) and the cause is the lower hardness values of PVP formulated tablets. This revelation is consistent with earlier finding ³¹. Furthermore, there is significant difference (p < 0.05) between the hardness values of the commercial paracetamol tablets and those formulated with the novel excipients, and this resulted from the much lower hardness values of the commercial product. The much lower hardness of the commercial product is not a disadvantage since it displayed lower friability and disintegration time than the tablets formulated with the novel excipients. The mean disintegration times for tablets formulated with the physical mixtures ranged from 10.81 min (PCPM – M₁) to 13.24 min PCPM – M₄), those of tablets formulated with the novel excipients ranged from 10.33 min (PCL₂M₁T₃₀) to 13.81 min (PCL₃M₅T₁₀), while those of commercial product and tablets formulated with PVP  were 4.06 min and 12.88 min respectively. The short disintegration time of the commercial product is a plus to the product; however, observation of the disintegration process reveals that a superdisintegrant might have been one of the ingredients used in its production. It is however worthy to note that the disintegration times of all the tablets studied were within the stipulated standard of ≤ 15 min  for conventional tablets ¹⁷. No statistical difference exists between the disintegration times of tablets formulated with the physical mixtures, those formulated with the novel excipients and those formulated with PVP as was revealed by ANOVA; and since PVP is an acceptable and a very popular binder in the formulation of conventional tablets ^{30, 31, 32}, the novel excipients can be adjudged to have done creditably well in comparison to PVP.

 

The dissolution profiles of some of the paracetamol tablets studied are shown in Fig. 3. The least cumulative amount of drug released after 60 min was 85.7% (PCPM – M₅), and the next was 88.6% (PCL₂M₅T₁₀ and PCL₂M₅T₃₀). Among the products containing the novel excipients, PCL₁M₅T₆₀ released the highest amount of drug (96.6%) in 60 min. The explanation of this observation is not apparent although it may be ascribed to the rate at which granule disintegration took place for the different formulations. Tablets formulated with PVP released up to 99.4% while the commercial product yielded 114.7% of the drug in 60 min. The recommended time to release at least 70% of active ingredient from conventional tablets is 30 min and this was met by tablets formulated with PVP, commercial product and all the tablets formulated with the novel excipients or the physical mixture. Consequently, it is evident that novel excipients as well as the physical mixtures of their components are useable in the wet granulation process for the formulation of a large dose active ingredient that is even elastic in nature and  compares favourably well with a popular standard.   

 

CONCLUSION:

The Lacagpregs have proved their usefulness in tablet formulation via both wet granulation and direct compression methods. In the direct compression method, just few of them were useable for the test drugs; in contrast, all of them, including the physical mixtures of their components were useable for tablet formulation by wet granulation. It is however important to note that binder concentration and duration of agitation influenced the functionality of the excipients in the tablets, whereas the degree of agitation had no remarkable influence on their effectiveness as multifunctional excipients. Finally, the qualities of the tablets formulated with the new excipients compared very favourably with those of similar tablets formulated with versatile standard tablet excipients and popular commercial products available in Nigeria.

 

ACKNOWLEDGEMENT:

The authors are grateful to the technical staff in department of pharmaceutics and raw material research, national institute for pharmaceutical research and development Abuja, department of pharmaceutical technology and industrial pharmacy, Madonna university Elele, Rivers state, Nigeria, who rendered invaluable services during the course of this research.

 

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Accepted on 20.07.2013         © RJPT All right reserved